Novel compounds as opioid receptor modulators

ABSTRACT

The present invention is directed to novel opioid receptor modulators of Formula (I). 
     
       
         
         
             
             
         
       
     
     The invention further relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 14/045,008, filed Oct. 3, 2013 (now allowed), which is a continuation of U.S. Ser. No. 13/690,041, filed Nov. 30, 2012 (now U.S. Pat. No. 8,609,709), which is a divisional of U.S. Ser. No. 12/838,825, filed Jul. 19, 2010 (now U.S. Pat. No. 8,344,011), which is a divisional of U.S. Ser. No. 11/877,747, filed Oct. 24, 2007 (now U.S. Pat. No. 7,786,158), which is a continuation of U.S. Ser. No. 11/079,647, filed Mar. 14, 2005 (now U.S. Pat. No. 7,741,356), which claims the benefit of U.S. Provisional App. No. 60/553,342, filed Mar. 15, 2004, the entire contents of each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention is directed to novel opioid receptor modulators of Formula (I). The invention further relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their use in the treatment of opioid modulated disorders.

BACKGROUND OF THE INVENTION

The opioid receptors were identified in the mid-1970's, and were quickly categorized into three sub-sets of receptors (mu, delta and kappa). More recently the original three types of receptors have been further divided into sub-types. Also known is that the family of opioid receptors are members of the G-protein coupled receptor (GPCR) super-family. More physiologically pertinent are the well established facts that opioid receptors are found throughout the central and peripheral nervous system of many mammalian species, including humans, and that modulation of the respective receptors can elicit numerous, albeit different, biological effects, both desirable and undesirable (D. S. Fries, “Analgesics”, in Principles of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269; J. V. Aldrich, “Analgesics”, Burger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Volume 3: Therapeutic Agents, John Wiley & Sons, Inc., 1996, pp. 321-441). In the most current literature, the likelihood of heterodimerization of the sub-classes of opioid receptors has been reported, with respective physiological responses yet undetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development”, Drug Development 2000, pp. 203-238).

A couple biological effects identified for opioid modulators have led to many useful medicinal agents. Most significant are the many centrally acting mu opioid agonist modulators marketed as analgesic agents to attenuate pain (e.g., morphine), as well as peripherally acting mu agonists to regulate motility (e.g., loperamide). Currently, clinical studies are continuing to evaluate medicinal utility of selective delta, mu, and kappa modulators, as well as compounds possessing combined sub-type modulation. It is envisioned such explorations may lead to agents with new utilities, or agents with minimized adverse side effects relative to currently available agents (examples of side effects for morphine includes constipation, respiratory depression, and addiction potential). Some new GI areas where selective or mixed opioid modulators are currently being evaluated includes potential treatment for various diarrheic syndromes, motility disorders (post-operative ileus, constipation), and visceral pain (post operative pain, irritable bowel syndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, the enkephalins were identified as a set of endogenous opioid ligands (D. S. Fries, “Analgesics”, in Principles of Medicinal Chemistry, 4th ed.; W. O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncating the original pentapeptide enkephalins to simplified dipeptides yielded a series of compounds that maintained opioid activity (Schiller, P. WO 96/06855). However one potential drawback cited for such compounds is the likelihood of their inherent instability (P. W. Schiller et al., Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containing heteroaromatic or heteroaliphatic nuclei were disclosed, however this series is reported showing a different functional profile than that described in the Schiller works. (L. H. Lazarus et al., Peptides 2000, 21, pp. 1663-1671)

Most recently, works around morphine related structures were reported by Wentland, et al, where carboxamido morphine derivatives and it's analogs were prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 623-626). Wentland found that substitution for the phenol moiety of the morphine related structures with a primary carboxamide led anywhere from equal activities up to 40 fold reduced activities, depending on the opioid receptor and the carboxamide. It was also revealed that any additional N-substitutions on the carboxamide significantly diminished the desired binding activity.

Compounds of the present invention have not been previously disclosed and are believed to provide advantages over related compounds by providing improved pharmacological profiles.

Opioid receptor modulators, agonists or antagonists are useful in the treatment and prevention of various mammalian disease states, for example pain and gastrointestinal disorders such as diarrheic syndromes, motility disorders including post-operative ileus and constipation, and visceral pain including post-operative pain, irritable bowel syndrome and inflammatory bowel disorders.

It is an object of the present invention to provide opioid receptor modulators. It is a further object of the invention to provide opioid receptor agonists and opioid receptor antagonists. It is an object of the present invention to provide opioid receptor ligands that are selective for each type of opioid receptor, mu, delta and kappa. It is a further object of the present invention to provide opioid receptor ligands that modulate two or three opioid receptor types, mu, delta and kappa, simultaneously. It is an object of the invention to provide certain instant compounds that are also useful as intermediates in preparing new opioid receptor modulators. It is also an object of the invention to provide a method of treating or ameliorating a condition mediated by an opioid receptor. And, it is an object of the invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as an opioid receptor modulator.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula (I)

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl,         cycloalkyl, heterocyclyl, aryl(C₁₋₆)alkyl, and         heteroaryl(C₁₋₆)alkyl; wherein aryl of aryl(C₁₋₆)alkyl is         optionally fused to a heterocyclyl or cycloalkyl;     -   and wherein the cycloalkyl and heterocyclyl of R¹ are optionally         substituted with C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy,         hydroxy, cyano, amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino,         halogen, carboxy, aryl(C₁₋₆)alkoxycarbonyl, C₁₋₆alkoxycarbonyl,         aminocarbonyl, C₁₋₆alkylaminocarbonyl,         (C₁₋₆alkyl)₂aminocarbonyl, or aminosulfonyl;     -   and, wherein C₁₋₆alkyl of R¹ is optionally substituted with one         to three substituents independently selected from the group         consisting of C₁₋₆alkoxy, aryl, cycloalkyl, heterocyclyl,         hydroxy, cyano, amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino,         halogen, and carboxy;     -   and wherein the aryl and heteroaryl portion of aryl(C₁₋₆)alkyl         and heteroaryl(C₁₋₆)alkyl are optionally substituted with one to         three R¹¹ substituents independently selected from the group         consisting of C₁₋₆alkyl; hydroxy(C₁₋₆)alkyl; C₁₋₆alkoxy;         aryl(C₁₋₆)alkyl; aryl(C₁₋₆)alkoxy; aryl; heteroaryl optionally         substituted with C₁₋₆alkyl; cycloalkyl; heterocyclyl; aryloxy;         heteroaryloxy; cycloalkyloxy; heterocyclyloxy; amino;         C₁₋₆alkylamino; (C₁₋₆alkyl)₂amino; C₁₋₆cycloalkylaminocarbonyl;         hydroxy(C₁₋₆)alkylaminocarbonyl; arylaminocarbonyl wherein aryl         is optionally substituted with carboxy or C₁₋₆alkoxycarbonyl;         heterocyclylcarbonyl; carboxy; C₁₋₆alkoxycarbonyl;         C₁₋₆alkylcarbonyl; C₁₋₆alkylcarbonylamino; aminocarbonyl;         C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl; cyano;         halogen; trifluoromethyl; trifluoromethoxy; or hydroxy;     -   R² is selected from the group consisting of hydrogen, C₁₋₈alkyl,         hydroxy(C₁₋₈)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, or aryl(C₁₋₈)alkyl;         -   wherein the aryl portion of the aryl-containing substituents             of R² are optionally substituted with one to two             substituents independently selected from the group             consisting of C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, amino,             C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, aminocarbonyl,             C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, cyano,             fluoro, chloro, bromo, trifluoromethyl, and             trifluoromethoxy; and wherein alkyl and alkoxy substituents             of aryl are optionally substituted with hydroxy, amino,             C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, or aryl;     -   A is selected from the group consisting of aryl, ring system         a-1, a-2, a-3, and a-4, optionally substituted with Wand R⁵;

-   -   -   wherein         -   A-B is selected from the group consisting of N—C, C—N, N—N             and C—C;         -   D-E is selected from the group consisting of O—C, S—C, and             O—N;

    -   R³ is one to two substituents independently selected from the         group consisting of C₁₋₆alkyl, aryl, aryl(C₁₋₆)alkyl,         aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, heteroaryl,         heteroaryl(C₁₋₆)alkyl, heteroaryl(C₂₋₆)alkenyl,         heteroaryl(C₂₋₆)alkynyl, amino, C₁₋₆alkylamino,         (C₁₋₆alkyl)₂amino, arylamino, heteroarylamino, aryloxy,         heteroaryloxy, and halogen;

    -   wherein the aryl and heteroaryl portion of R³ are optionally         substituted with one to five substituents independently selected         from the group consisting of C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl,         C₁₋₆alkoxy, aryl(C₁₋₆)alkyl, aryl(C₁₋₆)alkoxy, aryl, aryloxy,         heteroaryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkoxy, heteroaryl,         heteroaryloxy, arylamino, heteroarylamino, amino,         C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, carboxy(C₁₋₆)alkylamino,         carboxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,         C₁₋₆alkylcarbonylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl,         (C₁₋₆alkyl)₂aminocarbonyl, carboxy(C₁₋₆)alkylaminocarbonyl,         cyano, halogen, trifluoromethyl, trifluoromethoxy, hydroxy,         C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonylamino,         —C(O)—NH—CH(—R^(c))—C(O)—NH₂, and C₁₋₆alkyl;

    -   wherein C₁₋₆alkyl of R³ is optionally substituted with a         substituent selected from the group consisting of hydroxy,         carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₆alkylamino,         (C₁₋₆alkyl)₂amino, aminocarbonyl, (C₁₋₄)alkylaminocarbonyl,         di(C₁₋₄)alkylaminocarbonyl, aryl, heteroaryl, arylamino,         heteroarylamino, aryloxy, heteroaryloxy, aryl(C₁₋₄)alkoxy, and         heteroaryl(C₁₋₄ alkoxy;

    -   R^(c) is selected from the group consisting of hydrogen,         C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,         C₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl,         aryl, and heteroaryl;

    -   R⁴ is aryl or heteroaryl; wherein R⁴ is optionally substituted         with one to five substituents independently selected from the         group R⁴¹; wherein R⁴¹ is (C₁₋₆)alkyl, (C₁₋₆)alkoxy,         aryl(C₁₋₆)alkoxy, aryl(C₁₋₆)alkylcarbonyloxy,         heteroaryl(C₁₋₆)alkylcarbonyloxy, heteroaryl, hydroxy, halogen,         aminosulfonyl, formylamino, aminocarbonyl,         C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl,         heterocyclylcarbonyl, carboxy, or cyano; and wherein C₁₋₆alkyl         is optionally substituted with amino, C₁₋₆alkylamino, or         (C₁₋₆alkyl)₂amino; and wherein the aryl portion of         aryl(C₁₋₆)alkylcarbonyloxy is optionally substituted with one to         four substituents independently selected from the group         consisting of (C₁₋₆)alkyl, (C₁₋₆)alkoxy, halogen, cyano, amino,         and hydroxy;

    -   R⁵ is a substituent on a nitrogen atom contained in ring A         selected from the group consisting of hydrogen, C₁₋₄alkyl, and         aryl;

    -   R⁶ is selected from the group consisting of hydrogen and         C₁₋₆alkyl;

    -   R⁷ is selected from the group consisting of hydrogen and         C₁₋₆alkyl;

    -   R^(a) and R^(b) are substituents independently selected from the         group consisting of hydrogen and C₁₋₆alkyl; or, when R^(a) and         R^(b) are other than hydrogen, R^(a) and R^(b) are optionally         taken together with the nitrogen to which they are both attached         to form a five to eight membered monocyclic ring;

    -   L is selected from the group consisting of O, S, and N(R^(d));         wherein R^(d) is hydrogen, C₁₋₆alkyl, or aryl;

    -   and pharmaceutically acceptable enantiomers, diastereomers,         racemates, and salts thereof.

The present invention is also directed to compounds of Formula (I)

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl,         cycloalkyl, heterocyclyl, aryl(C₁₋₆)alkyl, and         heteroaryl(C₁₋₆)alkyl; wherein when R¹ is phenyl(C₁₋₆)alkyl,         phenyl is optionally fused to a heterocyclyl or cycloalkyl;     -   wherein when R¹ is C₁₋₂alkyl, said C₁₋₂alkyl is optionally         substituted with one to two substituents independently selected         from the group consisting of C₁₋₆alkoxy, aryl, cycloalkyl,         heterocyclyl, hydroxy, cyano, amino, C₁₋₆alkylamino,         (C₁₋₆alkyl)₂amino, trifluoromethyl, and carboxy;     -   and further, wherein when R¹ is C₃₋₆alkyl, said C₃₋₆alkyl is         optionally substituted with one to three substituents         independently selected from the group consisting of C₁₋₆alkoxy,         aryl, cycloalkyl, heterocyclyl, hydroxy, cyano, amino,         C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, trifluoromethyl, and carboxy;     -   wherein the cycloalkyl and heterocyclyl of C₁₋₂alkyl and         C₃₋₆alkyl are optionally substituted with one to two         substituents independently selected from the group consisting of         C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy, hydroxy, cyano,         amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, trifluoromethyl,         carboxy, aryl(C₁₋₆)alkoxycarbonyl, C₁₋₆alkoxycarbonyl,         aminocarbonyl, C₁₋₆alkylaminocarbonyl,         (C₁₋₆alkyl)₂aminocarbonyl, and aminosulfonyl;     -   furthermore, wherein the cycloalkyl and heterocyclyl of R¹ are         optionally substituted with one to two substituents         independently selected from the group consisting of C₁₋₆alkyl,         hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy, hydroxy, cyano, amino,         C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, trifluoromethyl, carboxy,         aryl(C₁₋₆)alkoxycarbonyl, C₁₋₆alkoxycarbonyl, aminocarbonyl,         C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, and         aminosulfonyl;     -   furthermore, wherein the aryl and heteroaryl portion of the R¹         substituents aryl(C₁₋₆)alkyl and heteroaryl(C₁₋₆)alkyl, are         optionally substituted with one to three R¹¹ substituents         independently selected from the group consisting of C₁₋₆alkyl;         hydroxy(C₁₋₆)alkyl; C₁₋₆alkoxy; C₆₋₁₀aryl(C₁₋₆)alkyl;         C₆₋₁₀aryl(C₁₋₆)alkoxy; C₆₋₁₀aryl; heteroaryl optionally         substituted with one to two substituents independently selected         from the group consisting of C₁₋₄alkoxy, and carboxy;         cycloalkyl; heterocyclyl; C₆₋₁₀aryloxy; heteroaryloxy;         cycloalkyloxy; heterocyclyloxy; amino; C₁₋₆alkylamino;         (C₁₋₆alkyl)₂amino; C₃₋₆cycloalkylaminocarbonyl;         hydroxy(C₁₋₆)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl wherein         C₆₋₁₀aryl is optionally substituted with carboxy or         C₁₋₄alkoxycarbonyl; heterocyclylcarbonyl; carboxy;         C₁₋₆alkylcarbonyloxy; C₁₋₆alkoxycarbonyl; C₁₋₆alkylcarbonyl;         C₁₋₆alkylcarbonylamino; aminocarbonyl; C₁₋₆alkylaminocarbonyl;         (C₁₋₆alkyl)₂aminocarbonyl; cyano; halogen; trifluoromethyl;         trifluoromethoxy; and hydroxy;         -   provided that no more than one R¹¹ substituent is selected             from the group consisting of C₆₋₁₀aryl(C₁₋₆)alkyl;             C₆₋₁₀aryl(C₁₋₆)alkoxy; C₆₋₁₀aryl; heteroaryl optionally             substituted with one to two substituents independently             selected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,             and carboxy; cycloalkyl; heterocyclyl; C₆₋₁₀aryloxy;             heteroaryloxy; cycloalkyloxy; C₆₋₁₀arylaminocarbonyl,             heterocyclylcarbonyl; and heterocyclyloxy;     -   R² is hydrogen, C₁₋₈alkyl, hydroxy(C₁₋₈)alkyl,         C₆₋₁₀aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, or C₆₋₁₀aryl(C₁₋₈)alkyl;         -   wherein the C₆₋₁₀aryl group in the C₆₋₁₀aryl-containing             substituents of R² are optionally substituted with one to             two substituents independently selected from the group             consisting of C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, amino,             C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, aminocarbonyl,             C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, cyano,             fluoro, chloro, bromo, trifluoromethyl, and             trifluoromethoxy; and, wherein the C₁₋₆alkyl and C₁₋₆alkoxy             substituents of aryl are optionally substituted with             hydroxy, amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino, or C1-6             aryl;     -   A is selected from the group consisting of aryl, ring system         a-1, a-2, a-3, and a-4, optionally substituted with R³ and R⁵;

-   -   -   wherein         -   A-B is selected from the group consisting of N—C, C—N, N—N             and C—C;         -   D-E is selected from the group consisting of O—C, S—C, and             O—N;         -   F-G is selected from the group consisting of N—O and C—O;

    -   R³ is one to two substituents independently selected from the         group consisting of C₁₋₆alkyl, aryl, aryl(C₁₋₆)alkyl,         aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, heteroaryl,         heteroaryl(C₁₋₆)alkyl, heteroaryl(C₂₋₆)alkenyl,         heteroaryl(C₂₋₆)alkynyl, amino, C₁₋₆alkylamino,         (C₁₋₆alkyl)₂amino, arylamino, heteroarylamino, aryloxy,         heteroaryloxy, trifluoromethyl, and halogen;         -   wherein the aryl, heteroaryl and the aryl and heteroaryl of             aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl,             heteroaryl(C₁₋₆)alkyl, heteroaryl(C₂₋₆)alkenyl,             heteroaryl(C₂₋₆)alkynyl, arylamino, heteroarylamino,             aryloxy, and heteroaryloxy, are optionally substituted with             one to five fluoro substituents or one to three substituents             independently selected from the group consisting of             C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy,             C₆₋₁₀aryl(C₁₋₆)alkyl, C₆₋₁₀aryl(C₁₋₆)alkoxy, C₆₋₁₀aryl,             C₆₋₁₀aryloxy, heteroaryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkoxy,             heteroaryl, heteroaryloxy, C₆₋₁₀arylamino, heteroarylamino,             amino, C₁₋₆alkylamino, (C₁₋₆alkyl)₂amino,             carboxy(C₁₋₆)alkylamino, carboxy, C₁₋₆alkylcarbonyl,             C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, aminocarbonyl,             C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl,             carboxy(C₁₋₆)alkylaminocarbonyl, cyano, halogen,             trifluoromethyl, trifluoromethoxy, hydroxy,             C₁₋₆alkylsulfonyl, and C₁₋₆alkylsulfonylamino; provided that             no more than one such substituent on the aryl or heteroaryl             portion of R³ is selected from the group consisting of             C₆₋₁₀aryl(C₁₋₆)alkyl, C₆₋₁₀aryl(C₁₋₆)alkoxy, C₆₋₁₀aryl,             C₆₋₁₀aryloxy, heteroaryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkoxy,             heteroaryl, heteroaryloxy, C₆₋₁₀arylamino, and             heteroarylamino;         -   and wherein C₁₋₆alkyl, and C₁₋₆alkyl of aryl(C₁₋₆)alkyl and             heteroaryl(C₁₋₆)alkyl is optionally substituted with a             substituent selected from the group consisting of hydroxy,             carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₆alkylamino,             (C₁₋₆alkyl)₂amino, aminocarbonyl, (C₁₋₄)alkylaminocarbonyl,             di(C₁₋₄)alkylaminocarbonyl, aryl, heteroaryl, arylamino,             heteroarylamino, aryloxy, heteroaryloxy, aryl(C₁₋₄)alkoxy,             and heteroaryl(C₁₋₄)alkoxy;

    -   R⁴ is C₆₋₁₀aryl or a heteroaryl selected from the group         consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,         imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,         indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,         benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl,         quinolinyl, isoquinolinyl and quinazolinyl;         -   wherein R⁴ is optionally substituted with one to three R⁴¹             substituents independently selected from the group             consisting of (C₁₋₆)alkyl optionally substituted with amino,             C₁₋₆alkylamino, or (C₁₋₆alkyl)₂amino; (C₁₋₆)alkoxy;             phenyl(C₁₋₆)alkoxy; phenyl(C₁₋₆)alkylcarbonyloxy wherein the             C1-6 alkyl is optionally substituted with amino; a non fused             5-membered-heteroaryl(C₁₋₆)alkylcarbonyloxy; a non fused             5-membered-heteroaryl; hydroxy; halogen; aminosulfonyl;             formylamino; aminocarbonyl; C₁₋₆alkylaminocarbonyl wherein             C₁₋₆alkyl is optionally substituted with amino,             C₁₋₆alkylamino, or (C₁₋₆alkyl)₂amino;             (C₁₋₆alkyl)₂aminocarbonyl wherein each C₁₋₆alkyl is             optionally substituted with amino, C₁₋₆alkylamino, or             (C₁₋₆alkyl)₂amino; heterocyclylcarbonyl wherein heterocyclyl             is a 5-7 membered nitrogen-containing ring and said             heterocyclyl is attached to the carbonyl carbon via a             nitrogen atom; carboxy; or cyano; and wherein the phenyl             portion of phenyl(C₁₋₆)alkylcarbonyloxy is optionally             substituted with (C₁₋₆)alkyl (C₁₋₆)alkoxy, halogen, cyano,             amino, or hydroxy;         -   provided that no more than one R⁴¹ is (C₁₋₆)alkyl             substituted with C₁₋₆alkylamino or (C₁₋₆alkyl)₂amino;             aminosulfonyl; formylamino; aminocarbonyl;             C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl;             heterocyclylcarbonyl; hydroxy; carboxy; or a phenyl- or             heteroaryl-containing substituent;

    -   R⁵ is a substituent on a nitrogen atom of ring A selected from         the group consisting of hydrogen and C₁₋₄alkyl;

    -   R⁶ is hydrogen or C₁₋₆alkyl;

    -   R⁷ is hydrogen or C₁₋₆alkyl;

    -   R^(a) and R^(b) are independently selected from the group         consisting of hydrogen, C₁₋₆alkyl, and C₁₋₆alkoxycarbonyl;         alternatively, when R^(a) and R^(b) are each other than         hydrogen, R^(a) and R^(b) are optionally taken together with the         nitrogen atom to which they are both attached to form a five to         eight membered monocyclic ring;

    -   L is selected from the group consisting of O, S, and N(R^(d))         wherein R^(d) is hydrogen or C₁₋₆alkyl;

    -   and pharmaceutically acceptable enantiomers, diastereomers,         racemates, and salts thereof.

Illustrative of the invention is a pharmaceutically acceptable carrier and any of the compounds described above.

The present invention is also directed to methods for producing the instant compounds of Formula (I) and pharmaceutical compositions and medicaments thereof.

The present invention is further directed to methods for treating opioid modulated disorders such as pain and gastrointestinal disorders. Compounds of the present invention are believed to provide advantages over related compounds by providing improved pharmacological profiles. Further specific embodiments of preferred compounds are provided hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic of the protocol to determine visceral hyperalgesia in rats.

FIG. 2 and FIG. 3 each show the effect in rat of Cpd 18 on the hyperalgesic response to colorectal balloon distention following zymosan.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include those compounds wherein R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl, aryl(C₁₋₄)alkyl, and heteroaryl(C₁₋₄)alkyl;

-   wherein the aryl and heteroaryl portion of aryl(C₁₋₄)alkyl and     heteroaryl(C₁₋₄)alkyl are optionally substituted with one to three     R¹¹ substituents independently selected from the group consisting of     C₁₋₆alkoxy; heteroaryl optionally substituted with one to two     substituents independently selected from the group consisting of     C₁₋₄alkyl, C₁₋₄alkoxy, and carboxy; carboxy; C₁₋₄alkoxycarbonyl;     C₁₋₄alkoxycarbonyloxy; aminocarbonyl; C₁₋₄alkylaminocarbonyl;     C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₆)alkylaminocarbonyl;     C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted     with carboxy or C₁₋₄alkoxycarbonyl; heterocyclylcarbonyl; cyano;     halogen; trifluoromethoxy; or hydroxy; provided that no more than     one R¹¹ is heteroaryl (optionally substituted with one to two     C₁₋₄alkyl substituents); C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is     optionally substituted with carboxy or C₁₋₄alkoxycarbonyl; or     heterocyclylcarbonyl.

Embodiments of the present invention include those compounds wherein R¹ is selected from the group consisting of C₆₋₁₀aryl(C₁₋₄)alkyl, pyridinyl(C₁₋₄)alkyl, and furanyl(C₁₋₄)alkyl; wherein C₆₋₁₀aryl, pyridinyl, and furanyl are optionally substituted with one to three R¹¹ substituents independently selected from the group consisting of C₁₋₃alkoxy; tetrazolyl; carboxy; C₁₋₄alkoxycarbonyl; aminocarbonyl; C₁₋₄alkylaminocarbonyl; C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₄)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted with carboxy or C₁₋₄alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano; halogen; and trifluoromethoxy; provided that that no more than one R¹¹ is C₆₋₁₀arylaminocarbonyl.

Embodiments of the present invention include those compounds wherein R¹ is selected from the group consisting of phenyl(C₁₋₃)alkyl, pyridinyl(C₁₋₃)alkyl, and furanyl(C₁₋₃)alkyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted with one to three R¹¹ substituents independently selected from the group consisting of C₁₋₃alkoxy; tetrazolyl, C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₄)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted with carboxy or C₁₋₄alkoxycarbonyl; morpholin-4-ylcarbonyl; chloro; fluoro; trifluoromethoxy; C₁₋₄alkoxycarbonyl; and carboxy; provided that that no more than one R¹¹ is C₆₋₁₀arylaminocarbonyl.

Embodiments of the present invention include those compounds wherein R¹ is phenylmethyl, pyridinylmethyl, or furanylmethyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted with one to three R¹¹ substituents independently selected from the group consisting of methoxy; tetrazolyl; cyclopropylaminocarbonyl; (2-hydroxyeth-1-yl)aminocarbonyl; methoxycarbonyl; phenylaminocarbonyl wherein phenyl is optionally substituted with carboxy; morpholin-4-ylcarbonyl; and carboxy; provided that that no more than one R¹¹ is phenylaminocarbonyl.

Embodiments of the present invention include those compounds wherein R² is a substituent selected from the group consisting of hydrogen, C₁₋₄alkyl, hydroxy(C₁₋₄)alkyl, and phenyl(C₁₋₆)alkoxy(C₁₋₄)alkyl; wherein said phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, cyano, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy.

Embodiments of the present invention include those compounds wherein R² is selected from the group consisting of hydrogen and C₁₋₄alkyl.

Embodiments of the present invention include those compounds wherein R² is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein ring A is a-1.

Embodiments of the present invention include those compounds wherein A-B of ring a-1 is selected from the group consisting of N—C and O—N.

Embodiments of the present invention include those compounds wherein A-B of ring a-1 is N—C.

Embodiments of the present invention include those compounds wherein R³ is one to two substituents independently selected from the group consisting of C₁₋₆alkyl, halogen, and aryl; wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, carboxy, aminocarbonyl, C₁₋₃alkylsulfonylamino, cyano, hydroxy, amino, C₁₋₃alkylamino, and (C₁₋₃alkyl)₂amino.

Embodiments of the present invention include those compounds wherein R³ is one to two substituents independently selected from the group consisting of C₁₋₃alkyl, bromo, and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, iodo, carboxy, aminocarbonyl, and cyano.

Embodiments of the present invention include those compounds wherein R³ is one to two substituents independently selected from the group consisting of methyl and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro and carboxy.

Embodiments of the present invention include those compounds wherein at least one R³ substituent is phenyl.

Embodiments of the present invention include those compounds wherein R³ is a substituent selected from the group consisting of methyl and phenyl optionally substituted with one to two substituents independently selected from the group consisting of chloro and carboxy.

Embodiments of the present invention include those compounds wherein R⁴ is C₆₋₁₀aryl optionally substituted with one to three R⁴¹ substituents independently selected from the group consisting of (C₁₋₃)alkyl, (C₁₋₆)alkoxy, phenyl(C₁₋₆)alkoxy; hydroxy; halogen; formylamino; aminocarbonyl; C₁₋₆alkylaminocarbonyl; (C₁₋₆alkyl)₂aminocarbonyl; heterocyclylcarbonyl wherein heterocyclyl is a 5-7 membered nitrogen-containing ring and said heterocyclyl is attached to the carbonyl carbon via a nitrogen atom; carboxy; and cyano; provided that no more than one R⁴¹ substituent is formylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl, heterocyclylcarbonyl, hydroxy, carboxy, or a phenyl-containing substituent.

Embodiments of the present invention include those compounds wherein R⁴ is phenyl substituted with one to three R⁴¹ substituents independently selected from the group consisting of (C₁₋₃)alkyl, (C₁₋₃)alkoxy, phenyl(C₁₋₃)alkoxy, hydroxy, C₁₋₆alkylaminocarbonyl, and aminocarbonyl; provided that no more than one R⁴¹ substitutent is aminocarbonyl, C₁₋₆alkylaminocarbonyl, hydroxy, or a phenyl-containing substituent.

Embodiments of the present invention include those compounds wherein R⁴ is phenyl substituted at the 4-position with hydroxy, C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and optionally substituted with one to two substituents independently selected from the group consisting of methyl, methoxy, and benzyloxy.

Embodiments of the present invention include those compounds wherein R⁴ is phenyl substituted at the 4-position with hydroxy, C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and optionally substituted with one to two methyl substituents.

Embodiments of the present invention include those compounds wherein R⁴ is phenyl substituted at the 4-position with hydroxy, C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and substituted at the 2- and 6-positions with methyl substituents.

Embodiments of the present invention include those compounds wherein R⁵ is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R⁵ is hydrogen.

Embodiments of the present invention include those compounds wherein R⁶ is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R⁶ is hydrogen.

Embodiments of the present invention include those compounds wherein R⁷ is hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R⁷ is hydrogen.

Embodiments of the present invention include those compounds wherein R^(a) and R^(b) are independently selected from the group consisting of hydrogen and C₁₋₃alkyl; or, when R^(a) and R^(b) are each other than hydrogen or C1-6 alkoxycarbonyl, R^(a) and R^(b) are optionally taken together with the nitrogen atom to which they are both attached to form a five to seven membered monocyclic ring.

Embodiments of the present invention include those compounds wherein R^(a) and R^(b) are independently hydrogen or methyl.

Embodiments of the present invention include those compounds wherein R^(a) and R^(b) are each hydrogen.

Embodiments of the present invention include those compounds wherein L is O.

Embodiments of the present invention include those compounds that are present in their RR, SS, RS, or SR configuration.

Embodiments of the present invention include those compounds that are present in their S,S configuration.

An aspect of the present invention includes compounds of Formula (Ia):

wherein: R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl, aryl(C₁₋₄)alkyl, and heteroaryl(C₁₋₄)alkyl;

-   wherein the aryl and heteroaryl portion of aryl(C₁₋₄)alkyl and     heteroaryl(C₁₋₄)alkyl are optionally substituted with one to three     R¹¹ substituents independently selected from the group consisting of     C₁₋₆alkoxy; heteroaryl optionally substituted with one to two     substituents independently selected from the group consisting of     C₁₋₄alkyl, C₁₋₄alkoxy, and carboxy; carboxy; C₁₋₄alkoxycarbonyloxy;     C₁₋₄alkoxycarbonyl; aminocarbonyl; C₁₋₄alkylaminocarbonyl;     C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₆)alkylaminocarbonyl;     C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted     with carboxy or C₁₋₄alkoxycarbonyl; heterocyclylcarbonyl; cyano;     halogen; trifluoromethoxy; and hydroxy; provided that no more than     one R¹¹ is heteroaryl (optionally substituted with one to two     C₁₋₄alkyl substituents); C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is     optionally substituted with carboxy or C₁₋₄alkoxycarbonyl; or     heterocyclylcarbonyl; -   R² is selected from the group consisting of hydrogen, C₁₋₄alkyl,     hydroxy(C₁₋₄)alkyl, and phenyl(C₁₋₆)alkoxy(C₁₋₄)alkyl; -   wherein said phenyl is optionally substituted with one to two     substituents independently selected from the group consisting of     C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, cyano, fluorine, chlorine, bromine,     trifluoromethyl, and trifluoromethoxy; -   R³ is one to two substituents independently selected from the group     consisting of C₁₋₆alkyl, halogen, and aryl; wherein aryl is     optionally substituted with one to three substituents independently     selected from the group consisting of halogen, carboxy,     aminocarbonyl, C₁₋₃alkylsulfonylamino, cyano, hydroxy, amino,     C₁₋₃alkylamino, and (C₁₋₃alkyl)₂amino; -   R⁴ is C₆₋₁₀aryl optionally substituted with one to three R⁴¹     substituents independently selected from the group consisting of     (C₁₋₃)alkyl, C₁₋₆)alkoxy, phenyl(C₁₋₆)alkoxy; hydroxy; halogen;     formylamino; aminocarbonyl; C₁₋₆alkylaminocarbonyl;     (C₁₋₆alkyl)₂aminocarbonyl; heterocyclylcarbonyl wherein heterocyclyl     is a 5-7 membered nitrogen-containing ring and said heterocyclyl is     attached to the carbonyl carbon via a nitrogen atom; carboxy; and     cyano;     provided that no more than one R⁴¹ substituent is formylamino,     aminocarbonyl, C₁₋₆alkylaminocarbonyl, (C₁₋₆alkyl)₂aminocarbonyl,     heterocyclylcarbonyl, hydroxy, carboxy, or a phenyl-containing     substituent.     R⁵ is hydrogen or methyl; -   R^(a) and R^(b) are independently hydrogen or C₁₋₃alkyl; or, when     R^(a) and R^(b) are each other than hydrogen, R^(a) and R^(b) are     optionally taken together with the nitrogen atom to which they are     both attached to form a five to seven membered monocyclic ring;     and pharmaceutically acceptable enantiomers, diastereomers,     racemates, and salts thereof.

Another aspect of the present invention is directed to a compound of Formula (Ia) wherein:

-   R¹ is selected from the group consisting of C₆₋₁₀aryl(C₁₋₄)alkyl,     pyridinyl(C₁₋₄)alkyl, and furanyl(C₁₋₄)alkyl; wherein C₆₋₁₀aryl,     pyridinyl, and furanyl are optionally substituted with one to three     R¹¹ substituents independently selected from the group consisting of     C₁₋₃alkoxy; tetrazolyl; carboxy; C₁₋₃alkoxycarbonyl; aminocarbonyl;     C₁₋₄alkylaminocarbonyl; C₁₋₃alkylaminocarbonyl;     C₃₋₆cycloalkylaminocarbonyl; hydroxy(C₁₋₄)alkylaminocarbonyl;     C₆₋₁₀arylaminocarbonyl wherein C₆₋₁₀aryl is optionally substituted     with carboxy or C₁₋₄alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano;     halogen; and trifluoromethoxy; provided that no more than one R¹¹ is     C₆₋₁₀arylaminocarbonyl; -   R² is hydrogen or C₁₋₄alkyl; -   R³ is one to two substituents independently selected from the group     consisting of C₁₋₃alkyl, bromo, and phenyl; wherein phenyl is     optionally substituted with one to three substituents independently     selected from the group consisting of chloro, fluoro, carboxy,     aminocarbonyl, and cyano; -   R⁴ is phenyl substituted with one to three R⁴¹ substituents     independently selected from the group consisting of (C₁₋₃)alkyl,     (C₁₋₃)alkoxy, phenyl(C₁₋₃)alkoxy, hydroxy, C₁₋₆alkylaminocarbonyl,     and aminocarbonyl; provided that no more than one R⁴¹ is     aminocarbonyl, C₁₋₆alkylaminocarbonyl, hydroxy, or a     phenyl-containing substituent; -   R⁵ is hydrogen; -   R^(a) and R^(b) are independently hydrogen or methyl; -   and pharmaceutically acceptable enantiomers, diastereomers,     racemates, and salts thereof.

Another aspect of the present invention is directed to a compound of Formula (Ia) wherein:

-   R¹ is selected from the group consisting of phenyl(C₁₋₃)alkyl,     pyridinyl(C₁₋₃)alkyl, and furanyl(C₁₋₃)alkyl; wherein phenyl,     pyridinyl, and furanyl are optionally substituted with one to three     R¹¹ substituents independently selected from the group consisting of     C₁₋₃alkoxy; tetrazolyl, C₃₋₆cycloalkylaminocarbonyl;     hydroxy(C₁₋₄)alkylaminocarbonyl; C₆₋₁₀arylaminocarbonyl wherein     C₆₋₁₀aryl is optionally substituted with carboxy or     C₁₋₄alkoxycarbonyl; morpholin-4-ylcarbonyl; chloro; fluoro;     trifluoromethoxy; and carboxy; -   R² is hydrogen or methyl; -   R³ is one to two substituents independently selected from the group     consisting of methyl and phenyl; wherein phenyl is optionally     substituted with one to three substituents independently selected     from the group consisting of chloro and carboxy; -   R⁴ is phenyl substituted at the 4-position with hydroxy,     C₁₋₃alkylaminocarbonyl, or aminocarbonyl, and optionally substituted     with one to two substituents independently selected from the group     consisting of methyl, methoxy, and benzyloxy; -   R⁵ is hydrogen; -   R^(a) and R^(b) are each hydrogen; -   and pharmaceutically acceptable enantiomers, diastereomers,     racemates, and salts thereof.

Another embodiment is directed to compounds of Formula (Ib):

wherein in one embodiment of this invention the variables are as previously defined. In another embodiment of the present invention L is oxygen and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependently selected from the group consisting of:

TABLE I Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b)   1 2-Aminocarbonyl- methyl phenyl H H 2,6-dimethyl-4- H    phenylmethyl aminocarbonyl   2 2-Cyano-phenyl methyl phenyl H H 2,6-dimethyl-4- H    methyl aminocarbonyl   3 2-Bromo-phenyl methyl phenyl H H 2,6-dimethyl-4- H    methyl aminocarbonyl   4 3-Carboxy-4- methyl phenyl H H 4-aminocarbonyl H    methoxy-phenyl    methyl   5 3-Carboxy-4- H phenyl H H 4-aminocarbonyl H    methoxy-phenyl    methyl   6 3-Carboxy-4- H phenyl H H 2,6-dimethyl-4- H    methoxy-phenyl aminocarbonyl    methyl   7 3- H phenyl H H 2,6-dimethyl-4- H    Methoxycarbonyl- aminocarbonyl    4-methoxy-    phenylmethyl   8 3-(1H-tetrazol-5- methyl phenyl H H 2,6-dimethyl-4- H    yl)-4-methoxy- aminocarbonyl    phenylmethyl   9 3- methyl phenyl H H 2,6-dimethyl-4- H   Methoxycarbonyl- aminocarbonyl   phenylmethyl  10 3-Methoxy methyl naphthalen-1-yl H H 2,6-dimethyl-4- H   carbonyl- aminocarbonyl   phenylmethyl  11 3-Carboxy- methyl naphthalen-1-yl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  12 3-Carboxy- methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  13 4-Carboxy- methyl naphthalen-1-yl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  14 3-Methoxy-4- methyl phenyl H H 2,6-dimethyl-4- H   carboxy- aminocarbonyl   phenylmethyl  15 3,4-Dihydroxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  16 Piperidin-4-yl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  17 3-Methoxy methyl phenyl H H 2,6-dimethyl-4- H   carbonyl-4- aminocarbonyl   methoxy--   phenylmethyl  18 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl-4- H   methoxy- aminocarbonyl   phenylmethyl  19 3,4-Dimethoxy- methyl 3-bromophenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  20 3,4-Dimethoxy- methyl 3-carboxyphenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  21 3,4-Dimethoxy- benzyloxy- phenyl H H 2,6-dimethyl-4- H   phenylmethyl methyl hydroxy  23 3,4-Dimethoxy- methyl 3-aminocarbonyl H H 2,6-dimethyl-4- H   phenylmethyl phenyl aminocarbonyl  24 3,4-Dimethoxy- methyl 3-cyanophenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  25 Isopropyl H quinoxalin-8-yl Me H 2,6-dimethyl-4- H   hydroxy  26 3,4-Dimethoxy- methyl 2-bromophenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  27 3,4-Dimethoxy- methyl 2-cyanophenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  28 3,4-Dimethoxy- methyl 2-aminocarbonyl H H 2,6-dimethyl-4- H   phenylmethyl phenyl aminocarbonyl  29 3,4-Dimethoxy- methyl 2-carboxyphenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  30 3,4-Dibenzyloxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  31 [1,3]benzo methyl phenyl H H 2,6-dimethyl, 4- H   dioxal-5-yl hydroxy  32 4-Methoxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  33 3-Methoxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  34 2,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  35 3,4-Dimethoxy- H phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  36 Isopropyl H 4-methylcarbonyl H H 2,6-dimethyl-4- H   phenyl hydroxy  37 Isopropyl H 3-fluoro, 4- Me H 2,6-dimethyl-4- H   carboxy-phenyl hydroxy  38 Isopropyl H 2-phenyl- Me H 2,6-dimethyl-4- H   ethylen-1-yl hydroxy  39 Isopropyl H 4-hydroxymethyl Me H 2,6-dimethyl-4- H   phenyl hydroxy  40 Benzhydryl H phenyl H H 2,6-dimethyl-4- H   hydroxy  41 Isopropyl H 4-cyanophenyl Me H 2,6-dimethyl-4- H   hydroxy  42 Benzyl methyl 4-trifluoromethyl H H 2,6-dimethyl-4- H   phenyl aminocarbonyl  43 Isopropyl H 3- Me H 2,6-dimethyl-4- H   trifluoromethoxy hydroxy   phenyl  44 Isopropyl H 4- Me H 2,6-dimethyl-4- H   trifluoromethoxy hydroxy   phenyl  45 Isopropyl H 3- Me H 2,6-dimethyl-4- H   methanesulfonyl hydroxy   aminophenyl  46 Isopropyl H 4-(2- Me H 2,6-dimethyl-4- H   carboxyethyl) hydroxy   phenyl  47 Isopropyl H 3-amino-5- Me H 2,6-dimethyl-4- H   carboxyphenyl hydroxy  48 3-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  49 4-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl carboxy  50 4-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  51 4-Methoxy methyl phenyl H H 2,6-dimethyl-4- H   carbonyl- aminocarbonyl   phenylmethyl  52 3-Methoxy methyl phenyl H H 2,6-dimethyl-4- H   carbonyl- hydroxy   phenylmethyl  53 1-Benzyloxy methyl phenyl H H 2,6-dimethyl-4- H   carbonyl- hydroxy   piperadin-4-   ylmethyl  54 Furan-2-yl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  55 Furan-3-yl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  56 Cyclohexyl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  57 Pyridin-4-yl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  58 Benzyl methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H   aminocarbonyl  59 Benzyl methyl 3-fluorophenyl H H 2,6-dimethyl-4- H   aminocarbonyl  60 Isopropyl H 3-cyanophenyl Me H 2,6-dimethyl-4- H   hydroxy  61 Isopropyl H 2,5-difluorophenyl Me H 2,6-dimethyl-4- H   hydroxy  62 Isopropyl H 4- Me H 2,6-dimethyl-4- H   methanesulfonyl hydroxy   phenyl  64 Benzyl benzyloxy phenyl H H 2,6-dimethyl-4- H   methyl aminocarbonyl  65 Isopropyl H Br Me H 2,6-dimethyl-4- H   hydroxy  66 Isopropyl H 4-dimethylamino Me H 2,6-dimethyl-4- H   phenyl hydroxy  67 Isopropyl H 3-dimethylamino Me H 2,6-dimethyl-4- H   carbonylphenyl hydroxy  68 Isopropyl H 3-hydroxyphenyl Me H 2,6-dimethyl-4- H   hydroxy  69 Isopropyl H 4-aminocarbonyl Me H 2,6-dimethyl-4- H   phenyl hydroxy  70 Isopropyl H 3-chlorophenyl Me H 2,6-dimethyl-4- H   hydroxy  71 Isopropyl H 2,4-difluorophenyl Me H 2,6-dimethyl-4- H   hydroxy  72 Isopropyl H 3- Me H 2,6-dimethyl-4- H   methanesulfonyl hydroxy   phenyl  73 Isopropyl H 3-aminocarbonyl Me H 2,6-dimethyl-4- H   phenyl hydroxy  74 Benzyl methyl 4-trifluoromethyl Me H 2,6-dimethyl-4- H   phenyl aminocarbonyl  75 3,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl aminocarbonyl  76 Benzyl methyl 4-fluorophenyl H H 2,6-dimethyl-4- H   aminocarbonyl  77 4-Dimethylamino- methyl phenyl H Me 2,6-dimethyl-4- H   phenylmethyl hydroxy  78 4-Methylamino- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  79 4-Methylcarbonyl methyl phenyl H H 2,6-dimethyl-4- H   amino-phenyl hydroxy   methyl  80 4-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  81 4-Hydroxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  83 Benzyl methyl 4-fluorophenyl H H 2,6-dimethyl-4- H   hydroxy  84 Isopropyl methyl 4-fluorophenyl H H 2,6-dimethyl-4- H   hydroxy  85 Isopropyl hydroxy phenyl H H 2,6-dimethyl-4- H   methyl aminocarbonyl  86 Isopropyl H phenyl H H 2,6-dimethyl, 4- H   aminocarbonyl  87 3,4-Dichloro- H phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  88 4-Methylcarbonyl methyl phenyl H H 2,6-dimethyl-4- H   oxy-phenyl hydroxy   methyl  89 4-Methoxy methyl phenyl H H 2,6-dimethyl-4- H   carbonyl- hydroxy   phenylmethyl  90 3-Aminocarbonyl- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  91 3-Cyano-phenyl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  92 Pyridin-3-yl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  93 Pyridin-2-yl methyl phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  94 1-(R)-Phenylethyl H phenyl H H 2,6-dimethyl-4- H   aminocarbonyl  95 1-(S)-Phenylethyl H phenyl H H 2,6-dimethyl-4- H   aminocarbonyl  96 2-Methoxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  97 2,6-Dichloro- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  98 3-Phenoxy- methyl phenyl H H 2,6-dimethyl-4- H   phenylmethyl hydroxy  99 Naphthalen-1-yl- methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 100 Naphthalen-2-yl- methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 101 3-Bromo-phenyl methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 102 3,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy 103 2,4-Dichloro- methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy 104 Benzyl isobutyl phenyl H H 2,6-dimethyl-4- H hydroxy 105 Benzyl benzyl phenyl H H 2,6-dimethyl-4- H hydroxy 106 Benzyl isopropyl phenyl H H 2,6-dimethyl-4- H hydroxy 107 Benzyl H phenyl H H 2,6-dimethyl-4- H aminocarbonyl 108 3-Phenyl methyl phenyl H H 2,6-dimethyl-4- H prop-1-yl aminocarbonyl 109 2-Phenylethyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 111 1-Phenylethyl methyl phenyl H H 2,6-dimethyl-4- H diastereomer A aminocarbonyl 112 1-Phenylethyl methyl phenyl H H 2,6-dimethyl-4- H diasteromer B aminocarbonyl 114 Benzyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 115 Isopropyl H 4-biphenyl Me H 2,6-dimethyl-4- H hydroxy 116 Isopropyl H 3-fluorophenyl Me H 2,6-dimethyl-4- H hydroxy 117 Isopropyl H 2-fluorophenyl Me H 2,6-dimethyl-4- H hydroxy 118 Isopropyl hydroxy phenyl H H 2,6-dimethyl-4- H methyl hydroxy 119 H hydroxy phenyl H H 2,6-dimethyl-4- H methyl hydroxy 120 Isopropyl 3-(amino phenyl H H 2,6-dimethyl-4- H methyl) hydroxy phenyl methyl 121 Isopropyl 3-amino phenyl H H 2,6-dimethyl-4- H carbonyl hydroxy phenyl methyl 122 Isopropyl 3-cyano phenyl H H 2,6-dimethyl-4- H phenyl hydroxy methyl 123 Isopropyl H 4-carboxyphenyl Me H 2,6-dimethyl-4- H hydroxy 124 Isopropyl H pyridin-3-yl Me H 2,6-dimethyl-4- H hydroxy 125 Isopropyl H 4-methoxyphenyl Me H 2,6-dimethyl-4- H hydroxy 126 Isopropyl H 3,5-difluorophenyl Me H 2,6-dimethyl-4- H hydroxy 127 Cyclohexyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 129 Carboxymethyl H phenyl H H 2,6-dimethyl-4- H hydroxy 130 Isopropyl H 3-hydroxymethyl Me H 2,6-dimethyl-4- H phenyl hydroxy 131 Isopropyl H pyrimidin-5-yl Me H 2,6-dimethyl-4- H hydroxy 132 Isopropyl H pyrimidin-5-yl Me H 4-hydroxy H 133 Isopropyl H 3-carboxyphenyl Me H 2,6-dimethyl-4- H hydroxy 134 Isopropyl H 3-biphenyl Me H 2,6-dimethyl-4- H hydroxy 135 Isopropyl H 2-methoxyphenyl Me H 2,6-dimethyl-4- H hydroxy 136 Isopropyl benzyl phenyl H H 3-aminocarbonyl H 137 Isopropyl isopropyl phenyl H H 3-aminocarbonyl H 138 Isopropyl benzyloxy phenyl H H 2,6-dimethyl-4- H methyl hydroxy 139 Isopropyl isobutyl phenyl H H 2,6-dimethyl-4-[2- H (2,6-dimethyl-4- hydroxyphenyl)-1- amino- ethylcarbonxyloxy] phenyl 140 Isopropyl isobutyl phenyl H H 2,6-dimethyl-4- H hydroxy 141 Isopropyl H 3,5- Me H 2,6-dimethyl-4- H dichlorophenyl hydroxy 142 Isopropyl H 3-methoxyphenyl Me H 2,6-dimethyl-4- H hydroxy 143 Isopropyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 145 Isopropyl H 2-biphenyl Me H 2,6-dimethyl-4- H hydroxy 146 Isopropyl H thiophen-3-yl Me H 2,6-dimethyl-4- H hydroxy 147 Isopropyl H 4-chlorophenyl Me H 2,6-dimethyl-4- H hydroxy 148 Isopropyl H 3-methylcarbonyl Me H 2,6-dimethyl-4- H aminophenyl hydroxy 149 Isopropyl H 4-trifluoromethyl Me H 2,6-dimethyl-4- H phenyl hydroxy 150 Isopropyl H naphthalen-2-yl Me H 2,6-dimethyl-4- H hydroxy 151 Isopropyl H 2-trifluoromethyl Me H 2,6-dimethyl-4- H phenyl hydroxy 152 Isopropyl H thiophen-3-yl Me H 4-hydroxy H 153 Isopropyl H pyridin-3-yl Me H 4-hydroxy H 154 Isopropyl H phenyl Me H 4-hydroxy H 155 Isopropyl H 2-chlorophenyl Me H 2,6-dimethyl-4- H hydroxy 156 Isopropyl H naphthalen-1-yl Me H 2,6-dimethyl-4- H hydroxy 157 Isopropyl benzyl phenyl H H 3-cyano H 158 Isopropyl benzyl phenyl H H 4-hydroxy H 159 Isopropyl benzyl phenyl H H 2,6-dimethyl-4- H hydroxy 160 Isopropyl isopropyl phenyl H H 3-cyano H 161 Isopropyl isopropyl phenyl H H 4-hydroxy H 162 Isopropyl isopropyl phenyl H H 2,6-dimethyl-4- H hydroxy 163 Isopropyl H 4-fluorophenyl Me H 2,6-dimethyl-4- H hydroxy 164 Isopropyl H 3,5-bis- Me H 2,6-dimethyl-4- H trifluoromethyl hydroxy phenyl 165 Isopropyl H 2-methylphenyl Me H 2,6-dimethyl-4- H hydroxy 166 Isopropyl H phenyl Me H 2,6-dimethyl-4- H hydroxy 167 2-Dimethylamino- H phenyl H H 2,6-dimethyl-4- H 1-methyl-eth-1-yl hydroxy 168 Methyl isobutyl phenyl H H 3-aminocarbonyl H 169 Methyl isobutyl phenyl H H 3-cyano H 170 Ethyl isopropyl phenyl H H 2,6-dimethyl-4- H hydroxy 171 Methyl isopropyl phenyl H H 4-hydroxy H 172 H 3-amino phenyl H H 2,6-dimethyl-4- H carbonyl hydroxy phenyl methyl 173 H 3-cyano phenyl H H 2,6-dimethyl-4- H phenyl hydroxy methyl 174 Methyl isobutyl phenyl H H 2,6-dimethyl-4- H hydroxy 175 H benzyloxy phenyl H H 2,6-dimethyl-4- H methyl hydroxy 176 H isobutyl phenyl H H 2,6-dimethyl-4- H hydroxy 177 H benzyl phenyl H H 2,6-dimethyl-4- H hydroxy 178 Isopropyl H phenyl H H 2,6-dimethyl-4- H aminocarbonyl 179 Methyl methyl phenyl H H 2,6-dimethyl-4- H morpholin-1- ylcarbonyl 181 Methyl methyl phenyl H H 2,6-dimethyl-4- H ethyl aminocarbonyl 183 Methyl methyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 185 H isopropyl phenyl H H 3-aminocarbonyl H 186 H isopropyl phenyl H H 3-cyano H 187 H isopropyl phenyl H H 2,6-dimethyl-4- H hydroxy 188 H isopropyl phenyl H H 4-hydroxy H 189 Methyl methyl phenyl H H 4-aminosulfonyl H 190 Cyclohexyl H phenyl H H 2,6-dimethyl-4- H hydroxy 191 Cyclohexyl H phenyl H H 4-hydroxy H 192 Cyclopropyl H phenyl H H 2,6-dimethyl-4- H methyl hydroxy 193 Cyclopropyl H phenyl H H 4-hydroxy H methyl 194 Isopropyl H phenyl H H 2,6-dimethyl-4- H hydroxy 195 Isopropyl H phenyl H H 4-hydroxy H 196 Methyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 197 Ethyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 198 Methyl H phenyl H H 4-hydroxy H 199 Methyl H phenyl H H 2,6-dimethyl-4- H hydroxy 202 Methyl methyl phenyl H H 4-aminocarbonyl H 204 Methyl methyl benzyl H H 4-hydroxy H 205 Methyl methyl benzyl H H 2,6-dimethyl-4- H hydroxy 207 Methyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 209 H methyl phenyl H H 2,6-dimethyl-4- H hydroxy 211 Methyl methyl phenyl H H 4-hydroxy H 213 H methyl phenyl H H 4-hydroxy H 215 Ethyl methyl phenyl H H 4-hydroxy H 216 Ethyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 218 Benzyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 219 Benzyl methyl phenyl H H 4-hydroxy H 224 Isopropyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 225 Isopropyl methyl phenyl H H 4-hydroxy H 226 2-Carboxy-phenyl methyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 227 3-Carboxy-phenyl methyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 229 2-Bromo-4,5- methyl phenyl H H 2,6-dimethyl-4- H dimethoxy- aminocarbonyl phenylmethyl 230 2-Carboxy-4,5- methyl phenyl H H 2,6-dimethyl-4- H dimethoxy- aminocarbonyl phenylmethyl 231 3-Carboxy-4- methyl phenyl H H H H methoxy-phenyl methyl 232 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl H methoxy-phenyl methyl 233 3- methyl phenyl H H 2,6-dimethyl H Methoxycarbonyl- 4-methoxy- phenylmethyl 234 3,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl imidazol-2-yl 236 3,4-Dimethoxy- methyl phenyl H H 2,6-dimethyl H phenylmethyl 237 3-Carboxy-4- methyl 4-chlorophenyl H H 2,6-dimethyl-4- H methoxy-phenyl aminocarbonyl methyl 238 3-Carboxy, 4- methyl 4-fluorophenyl H H 2,6-dimethyl-4- H methoxy-phenyl aminocarbonyl methyl 239 3-Carboxy-4- methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H methoxy-phenyl aminocarbonyl methyl 240 4-Carboxy-phenyl methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H methyl aminocarbonyl 241 3-Carboxy-4- methyl 4-chlorophenyl Cl H 2,6-dimethyl-4- H methoxy-phenyl aminocarbonyl methyl 242 3-(1H-tetrazol-5- methyl phenyl H H 2,6-dimethyl-4- H yl)-phenylmethyl aminocarbonyl 243 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl-4- H trifluoromethoxy- aminocarbonyl phenylmethyl 244 Bis-3,4- methyl phenyl H H 2,6-dimethyl-4- H trifluoromethoxy- aminocarbonyl phenylmethyl 245 3-Carboxy-phenyl methyl phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 246 Quinolin-4-yl methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 247 4-Methoxy methyl phenyl H H 2,6-dimethyl-4- H naphthalen-1- hydroxy ylmethyl 248 4- methyl phenyl H H 2,6-dimethyl-4- H Trifluoromethoxy- hydroxy phenylmethyl 249 4-Trifluoromethyl- methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy 250 4-Isopropyloxy- methyl phenyl H H 2,6-dimethyl-4- H phenylmethyl hydroxy 251 3-Ethoxyphenyl- methyl phenyl H H 2,6-dimethyl-4- H methyl hydroxy 252 5- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-2-ylmethyl 253 5-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H pyridin-2-ylmethyl aminocarbonyl 254 6-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H pyridin-3-ylmethyl aminocarbonyl 255 6- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-3-ylmethyl 256 5-Carboxy- methyl phenyl H H 2,6-dimethyl-4- H furan-2-ylmethyl aminocarbonyl 257 5- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl furan-2-ylmethyl 258 3,4-Dimethoxy- hydroxy phenyl H H 2,6-dimethyl-4- H phenylmethyl methyl aminocarbonyl 259 Benzyl hydroxy phenyl H H 2,6-dimethyl-4- H methyl aminocarbonyl 260 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl-4- H methoxy-phenyl hydroxy methyl 261 3-Carboxy-4- methyl phenyl H H 4-hydroxy H methoxy-phenyl methyl 262 3-Carboxy-4- methyl phenyl H H 4-hydroxy H/Me methoxy-phenyl methyl 263 3-Carboxy-4- H phenyl H H 4-hydroxy H methoxy-phenyl methyl 264 3-Carboxy-4- H phenyl H H 4-hydroxy H/Me methoxy-phenyl methyl 265 3-Carboxy-4- H phenyl H H 2,6-dimethyl-4- H methoxy-phenyl hydroxy methyl 266 3- methyl phenyl H H H H Methoxycarbonyl- 4-methoxy- phenylmethyl 267 3-(1H-tetrazol-5- methyl phenyl H H 4-aminocarbonyl H yl)-phenylmethyl 268 3- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- hydroxy 4-methoxy- phenylmethyl 269 3- methyl phenyl H H 4-aminocarbonyl H Methoxycarbonyl 270 3-Carboxy methyl phenyl H H 4-aminocarbonyl H 271 3- H phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl aminocarbonyl 272 3-Carboxy H phenyl H H 2,6-dimethyl-4- H aminocarbonyl 274 3-Carboxy-4- methyl phenyl H H 4-benzyloxy H/Me methoxy- phenylmethyl 275 3-Carboxy-4- methyl phenyl H H 4-aminocarbonyl H methoxy- phenylmethyl 277 3-Carboxy-phenyl methyl 4-chlorophenyl Me H 4-aminocarbonyl H 279 3- methyl phenyl H H 4-hydroxy H Methoxycarbonyl- 4-methoxy- phenylmethyl 286 5- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- hydroxy furan-2-ylmethyl 287 5-Carboxy-furan- methyl phenyl H H 2,6-dimethyl-4- H 2-ylmethyl hydroxy 288 3-Carboxy-4- methyl 3-bromophenyl H H 2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 289 3-Carboxy-4- methyl 4-iodophenyl H H 2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 290 3-Carboxy-4- methyl 2-bromophenyl H H 2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 291 3-Carboxy-4- methyl 4-bromophenyl H H 2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 292 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl H methoxy- phenylmethyl 293 3-Carboxy-4- methyl 4-chlorophenyl methyl H 4-hydroxy H methoxy- phenylmethyl 295 3-Aminocarbonyl- methyl phenyl H H 2,6-dimethyl-4- H 4-methoxy aminocarbonyl phenylmethyl 296 3-(Morpholin-4- methyl phenyl H H 2,6-dimethyl-4- H ylcarbonyl)-4- aminocarbonyl methoxy phenylmethyl 297 -3-Aminocarbonyl- methyl phenyl H H 4-hydroxy H 4-methoxy- phenylmethyl 298 3-(Morpholin-4- methyl phenyl H H 4-hydroxy H ylcarbonyl)-4- methoxy- phenylmethyl 299 3-(2-Hydroxy methyl phenyl H H 2,6-dimethyl-4- H eth-1-yl- aminocarbonyl aminocarbonyl)-4- methoxy phenylmethyl 300 3-(Cyclopropyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl)-4- aminocarbonyl methoxy- phenylmethyl 301 3-(Phenylamino methyl phenyl H H 2,6-dimethyl-4- H carbonyl)-4- aminocarbonyl methoxy- phenylmethyl 303 5- methyl phenyl H H 4-aminocarbonyl H Methoxycarbonyl- furan-2-ylmethyl 304 5-Carboxy-furan- methyl phenyl H H 4-aminocarbonyl H 2-ylmethyl 305 3-(Phenylamino methyl phenyl H H 2,6-dimethyl-4- H carbonyl)-4- hydroxy methoxy- phenylmethyl 306 3-(3- methyl phenyl H H 2,6-dimethyl-4- H carboxyphenyl hydroxy aminocarbonyl)-4- methoxy- phenylmethyl 307 3-(1H-Tetrazol-5- methyl phenyl H H 2,6-dimethyl-4- H yl)-4-methoxy- hydroxy phenylmethyl 308 3-(4- methyl phenyl H H 2,6-dimethyl-4- H Carboxyphenyl hydroxy aminocarbonyl)-4- methoxy- phenylmethyl 309 3-(2-t-Butyl- methyl phenyl H H 2,6-dimethyl-4- H tetrazol-5-yl)-4- aminocarbonyl methoxy- phenylmethyl 310 3- methyl phenyl H H 2,6-dimethyl-4- Methoxy Methoxycarbonyl- aminocarbonyl carbonyl 4-methoxy- phenylmethyl 311 2- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-4-ylmethyl 312 4- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-2-ylmethyl 313 6- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-2-ylmethyl 315 3- methyl phenyl H H 2,6-dimethyl-4- Methoxy Methoxycarbonyl- aminocarbonyl carbonyl 4-methoxy- phenylmethyl 316 2-Carboxy-pyridin- methyl phenyl H H 2,6-dimethyl-4- H 4-ylmethyl aminocarbonyl 317 6-Carboxy-pyridin- methyl phenyl H H 2,6-dimethyl-4- H 2-ylmethyl aminocarbonyl

Exemplified compounds of the present invention include compounds of Formula (Ic):

wherein in one embodiment of this invention the variables are as previously defined. In another embodiment of the present invention L is O and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependently selected from the group consisting of:

TABLE II Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b)  22 3,4-Dimethoxy- benzyloxy phenyl H H 2,6-dimethyl-4- H   phenylmethyl methyl hydroxy  63 Isopropyl hydroxy phenyl H H 2,6-dimethyl-4- H   methyl hydroxy  82 Isopropyl methyl 4-fluorophenyl H H 2,6-dimethyl-4- H hydroxy 110 2-Phenylethyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 113 Benzyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 128 Cyclohexyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 144 Methyl methyl phenyl H H 2,6-dimethyl-4- H aminocarbonyl 180 Methyl methyl phenyl H H 2,6-dimethyl-4- H (morpholin-4- ylcarbonyl) 182 Methyl methyl phenyl H H 2,6-dimethyl-4- H ethylamino carbonyl 184 Methyl methyl phenyl H H 2,6-dimethyl-4- H methylamino carbonyl 203 Methyl methyl phenyl H H 4-aminocarbonyl H 206 Methyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 208 H methyl phenyl H H 2,6-dimethyl-4- H hydroxy 210 Methyl methyl phenyl H H 4-hydroxy H 212 H methyl phenyl H H 4-hydroxy H 214 Ethyl methyl phenyl H H 4-hydroxy H 217 Ethyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 220 Benzyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 221 Benzyl methyl phenyl H H 4-hydroxy H 222 Isopropyl methyl phenyl H H 4-hydroxy H 223 Isopropyl methyl phenyl H H 2,6-dimethyl-4- H hydroxy 228 3-Carboxy-phenyl methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H methyl aminocarbonyl 276 3-Carboxy-phenyl methyl 4-chlorophenyl Me H 4-aminocarbonyl H 278 3-Carboxy-4- methyl 4-chlorophenyl Me H 2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 280 3- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl 4-methoxy- phenylmethyl 281 3- methyl phenyl H H 4-aminocarbonyl H Methoxycarbonyl- 4-methoxy- phenylmethyl 282 3-Carboxy-4- methyl phenyl H H 2,6-dimethyl-4- H methoxy- aminocarbonyl phenylmethyl 283 3-Carboxy-4- methyl phenyl H H 4-aminocarbonyl H methoxy- phenylmethyl 294 3-Carboxy-4- methyl 4-chlorophenyl Me H 4-hydroxy H methoxy- phenylmethyl 314 6- methyl phenyl H H 2,6-dimethyl-4- H Methoxycarbonyl- aminocarbonyl pyridin-2-ylmethyl 318 3-Carboxy-4- methyl 4-chlorophenyl H H 4-aminocarbonyl H methoxy- phenylmethyl

Another embodiment is directed to compositions comprised of a compound of Formula (Id):

wherein in one embodiment of this invention the variables are as previously defined. In another embodiment of the present invention L is oxygen and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependently selected from the group consisting of:

TABLE III Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b) 273 3-Carboxy-4- methyl phenyl H H 4- H methoxyphenyl amino- methyl carbonyl

Exemplified compounds of the present invention include compounds of Formula (Ie):

wherein in one embodiment of this invention the variables are as previously defined. In another embodiment of the present invention L is O and R¹, R², R³⁻¹, R³⁻², R⁵, R^(a), R^(b), and R⁴¹ are dependently selected from the group consisting of:

TABLE IV Cpd R¹ R² R³⁻¹ R³⁻² R⁵ R⁴¹ R^(a)/R^(b) 284 3- methyl phenyl H H 4- H Methoxycarbonyl- amino- 4-methoxy- carbonyl phenylmethyl 285 3-Carboxy-4- methyl phenyl H H 4- H methoxy- amino- phenylmethyl carbonyl

A further embodiment of the present invention includes representative compounds shown in Table V:

TABLE V Cpd 4

6

8

12

18

20

75

227

The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (January), 66, 1, 1). Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or as individual enantiomers or diasteromers by either stereospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers or diasteromers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers and enantiomers thereof are encompassed within the scope of the present invention.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

In general, under standard nomenclature rules used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylC₁-C₆ alkylamidoC₁-C₆alkyl” substituent refers to a group of the formula:

It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

An “independently” selected substituent refers to a group of substituents, wherein the substituents may be different. Therefore, designated numbers of carbon atoms (e.g. C₁₋₈) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

As used herein, unless otherwise noted, “alkyl” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range. The term “alkoxy” refers to an —Oalkyl substituent group, wherein alkyl is as defined supra. Similarly, the terms “alkenyl” and “alkynyl” refer to straight and branched carbon chains having 2 to 8 carbon atoms or any number within this range, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. An alkyl and alkoxy chain may be substituted on a carbon atom. In substituent groups with multiple alkyl groups such as (C₁₋₆alkyl)₂amino- the C₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “cycloalkyl” refers to saturated or partially unsaturated, monocyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atom members. Examples of such rings include, and are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. Alternatively, the cycloalkyl ring may be fused to a benzene ring (benzo fused cycloalkyl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen) to form a heteroaryl fused cycloalkyl.

The term “heterocyclyl” refers to a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are nitrogen, or a nonaromatic cyclic ring of 5 to 7 members in which zero, one or two members are nitrogen and up to two members are oxygen or sulfur; wherein, optionally, the ring contains zero to one unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to two unsaturated bonds. The term “heterocyclyl” includes a 5 to 7 membered monocyclic heterocyclic ring fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the same definition as above but absent the option of a further fused ring) or fused with the carbon of attachment of a cycloalkyl, cycloalkenyl or heterocyclyl ring to form a spiro moiety. For instant compounds of the invention, the carbon atom ring members that form the heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially saturated heterocyclyl ring. The term “heterocyclyl” also includes a 5 to 7 membered monocyclic heterocycle bridged to form bicyclic rings. Such compounds are not considered to be fully aromatic and are not referred to as heteroaryl compounds. Examples of heterocyclyl groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

The term “aryl” refers to an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl or anthracenyl. Preferred aryl groups for the practice of this invention are phenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic ring of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of 5 membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to three additional nitrogens. In the case of 6 membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the 6 membered ring has three nitrogens, at most two nitrogen atoms are adjacent. Optionally, the heteroaryl ring is fused to a benzene ring (benzo fused heteroaryl), a 5 or 6 membered heteroaryl ring (containing one of O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring (as defined supra but absent the option of a further fused ring). Examples of heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroaryl groups include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl, isoquinolinyl or quinazolinyl.

The term “arylalkyl” means an alkyl group substituted with an aryl group (e.g., benzyl, phenethyl). Similarly, the term “arylalkoxy” indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy).

The term “halogen” refers to fluorine, chlorine, bromine and iodine. Substituents that are substituted with multiple halogens are substituted in a manner that provides compounds, which are stable.

Whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) it shall be interpreted as including those limitations given above for “alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl, and alkoxy substituents the designated number of carbon atoms includes all of the independent member included in the range specified individually and all the combination of ranges within in the range specified. For example C₁₋₆ alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g. C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

The novel compounds of the present invention are useful opioid receptor modulators. In particular, certain compounds are opioid receptor agonists useful in the treatment or amelioration of conditions such as pain and gastrointestinal disorders. Examples of pain intended to be within the scope of the present invention include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, pain related to inflammation, progressive disease related pain, neuropathic pain and acute pain such as caused by acute injury, trauma or surgery and chronic pain such as caused by neuropathic pain conditions, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain syndromes or cluster or migraine headaches. Examples of gastrointestinal disorders intended to be within the scope of this invention include, but are not limited to, diarrheic syndromes, motility disorders such as diarrhea-predominant, or alternating irritable bowel syndrome, and visceral pain and diarrhea associated with inflammatory bowel disease including ulcerative colitis and Crohn's disease.

Examples of gastrointestinal disorders where opioid receptor (“OR”) antagonists are useful include constipation-predominant irritable bowel syndrome, post-operative ileus and constipation, including but not limited to the constipation associated with treatment of chronic pain with opiates. Modulation of more than one opioid receptor subtype is also useful as follows: a compound that is a mixed mu OR agonist and delta OR antagonist could have antidiarrheal properties without being profoundly constipating. A compound that is a mixed mu OR agonist and delta OR agonist are useful in cases of severe diarrhea that are refractory to treatment with pure mu OR agonists, or has additional utility in treating visceral pain associated with inflammation and diarrhea.

Accordingly, a compound of the present invention may be administered by any conventional route of administration including, but not limited to oral, nasal, pulmonary, sublingual, ocular, transdermal, rectal, vaginal and parenteral (i.e. subcutaneous, intramuscular, intradermal, intravenous etc.). It is currently preferred that the compounds of the present invention be administered via modes of administration other than pulmonary or parenteral administration. However, the preferred compounds provided in Table IV may be administered via pulmonary or parenteral modes of administration.

To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula (I) or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

In preparing a pharmaceutical composition of the present invention in liquid dosage form for oral, topical and parenteral administration, any of the usual pharmaceutical media or excipients may be employed. Thus, for liquid dosage forms, such as suspensions (i.e. colloids, emulsions and dispersions) and solutions, suitable carriers and additives include, but are not limited to, pharmaceutically acceptable wetting agents, dispersants, flocculation agents, thickeners, pH control agents (i.e. buffers), osmotic agents, coloring agents, flavors, fragrances, preservatives (i.e. to control microbial growth, etc.) and a liquid vehicle may be employed. Not all of the components listed above will be required for each liquid dosage form.

In solid oral preparations such as, for example, dry powders for reconstitution or inhalation, granules, capsules, caplets, gelcaps, pills and tablets (each including immediate release, timed release and sustained release formulations), suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidants, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.

The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg/kg to about 300 mg/kg (preferably from about 0.01 mg/kg to about 100 mg/kg; and, more preferably, from about 0.01 mg/kg to about 30 mg/kg) and may be given at a dosage of from about 0.01 mg/kg/day to about 300 mg/kg/day (preferably from about 0.01 mg/kg/day to about 100 mg/kg/day and more preferably from about 0.01 mg/kg/day to about 30 mg/kg/day). Preferably, the method for the treatment of conditions that may be mediated by opioid receptors described in the present invention using any of the compounds as defined herein, the dosage form will contain a pharmaceutically acceptable carrier containing between from about 0.01 mg to about 100 mg; and, more preferably, from about 5 mg to about 50 mg of the compound, and may be constituted into any form suitable for the mode of administration selected. The dosages, however, may be varied depending upon the requirement of the subjects, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means.

For preparing solid pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents and gildants. Suitable diluents include, but are not limited to, starch (i.e. corn, wheat, or potato starch, which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like. Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e. TYLOSE™ available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and antiadherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like. Suitable gildants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot, SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silica available from Degussa) and the like. Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active to form a solid preformulation composition containing a homogeneous mixture of the pharmaceutical active of the present invention, or a pharmaceutically acceptable salt thereof. Generally the preformulation will be formed by one of three common methods: (a) wet granulation, (b) dry granulation and (c) dry blending. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 mg to about 500 mg of the active ingredient of the present invention. The tablets or pills containing the novel compositions may also be formulated in multilayer tablets or pills to provide a sustained or provide dual-release products. For example, a dual release tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric materials such as shellac, cellulose acetate (i.e. cellulose acetate phthalate, cellulose acetate trimellitate), polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylate and ethylacrylate copolymers, methacrylate and methyl methacrylate copolymers and the like. Sustained release tablets may also be made by film coating or wet granulation using slightly soluble or insoluble substances in solution (which for a wet granulation acts as the binding agents) or low melting solids a molten form (which in a wet granulation may incorporate the active ingredient). These materials include natural and synthetic polymers waxes, hydrogenated oils, fatty acids and alcohols (i.e. beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and the like), esters of fatty acids metallic soaps, and other acceptable materials that can be used to granulate, coat, entrap or otherwise limit the solubility of an active ingredient to achieve a prolonged or sustained release product.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, but are not limited to aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable suspending agents for aqueous suspensions, include synthetic and natural gums such as, acacia, agar, alginate (i.e. propylene alginate, sodium alginate and the like), guar, karaya, locust bean, pectin, tragacanth, and xanthan gum, cellulosics such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, and combinations thereof, synthetic polymers such as polyvinyl pyrrolidone, carbomer (i.e. carboxypolymethylene), and polyethylene glycol; clays such as bentonite, hectorite, attapulgite or sepiolite; and other pharmaceutically acceptable suspending agents such as lecithin, gelatin or the like. Suitable surfactants include but are not limited to sodium docusate, sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235 and combinations thereof. Suitable deflocculating or dispersing agent include pharmaceutical grade lecithins. Suitable flocculating agent include but are not limited to simple neutral electrolytes (i.e. sodium chloride, potassium, chloride, and the like), highly charged insoluble polymers and polyelectrolyte species, water soluble divalent or trivalent ions (i.e. calcium salts, alums or sulfates, citrates and phosphates (which can be used jointly in formulations as pH buffers and flocculating agents). Suitable preservatives include but are not limited to parabens (i.e. methyl, ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol and the like. There are many liquid vehicles that may be used in liquid pharmaceutical dosage forms, however, the liquid vehicle that is used in a particular dosage form must be compatible with the suspending agent(s). For example, nonpolar liquid vehicles such as fatty esters and oils liquid vehicles are best used with suspending agents such as low HLB (Hydrophile-Lipophile Balance) surfactants, stearalkonium hectorite, water insoluble resins, water insoluble film forming polymers and the like. Conversely, polar liquids such as water, alcohols, polyols and glycols are best used with suspending agents such as higher HLB surfactants, clays silicates, gums, water soluble cellulosics, water soluble polymers and the like.

Furthermore, compounds of the present invention can be administered in an intranasal dosage form via topical use of suitable intranasal vehicles or via transdermal skin patches, the composition of which are well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the administration of a therapeutic dose will, of course, be continuous rather than intermittent throughout the dosage regimen.

Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever treatment of disorders that may be mediated or ameliorated by opioid receptors for a subject in need thereof.

The daily dose of a pharmaceutical composition of the present invention may be varied over a wide range from about 0.1 mg to about 7000 mg per adult human per day; most preferably the dose will be in the range of from about 0.7 mg to about 2100 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably, the range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day; and, most preferably, from about 0.01 mg/kg to about 30 mg/kg of body weight per day. Advantageously, a compound of the present invention may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.

Representative IUPAC names for the compounds of the present invention were derived using the AutoNom version 2.1 nomenclature software program provided by Beilstein Informationssysteme.

Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:

-   BOC=tert-butoxycarbonyl -   BuLi=n-butyllithium -   CBZ=benzyloxycarbonyl -   Cpd or Cmpd=compound -   d=day/days -   DIPEA=diisopropylethylamine -   DPPF=1,1′-bis(diphenylphosphino)ferrocene -   DPPP=1,3-Bis(diphenylphosphino)propane -   EDCI or EDC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide     hydrochloride -   EtOAc=ethyl acetate -   EtOH=ethanol -   h=hour/hours -   HMDS=1,1,3,3-Hexamethyldisilazane -   HOBt/HOBT=hydroxybenzotriazole -   M=molar -   MeCN=acetonitrile -   MeOH=methanol -   min=minutes -   PyBOP=Benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium     hexafluorophosphate -   rt/RT=room temperature -   TFA=trifluoroacetic acid -   OTf=triflate -   Ts=tosyl

Synthetic Methods

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.

The following schemes describe general synthetic methods whereby intermediate and target compounds of the present invention may be prepared. Additional representative compounds and stereoisomers, racemic mixtures, diasteromers and enantiomers thereof can be synthesized using the intermediates prepared in accordance to the general schemes and other materials, compounds and reagents known to those skilled in the art. All such compounds, stereoisomers, racemic mixtures, diasteromers and enantiomers thereof are intended to be encompassed within the scope of the present invention.

Certain intermediates and compounds of the present invention may be prepared according to the process outlined in Scheme A below.

A carboxylic acid of the formula A-1, available either commercially or prepared by reported protocols in the scientific literature, may be coupled to an α-aminoketone using standard peptide coupling conditions with a coupling agent such as EDCI and an additive such as HOBt to provide a compound of formula A-2. Compound A-2 may be condensed with an amine of the formula H₂N—R₅ or ammonium acetate and cyclized upon heating in acetic acid to a compound of formula A-4.

The protecting group of compound A-4 may be removed using conditions known to those skilled in the art that are appropriate for the particular protecting group to afford a compound of the formula A-6. For instance, hydrogenation in the presence of a palladium catalyst is one method for the removal of a CBZ protecting group, whereas treatment with an acid such as TFA is effective for a BOC group deprotection.

A compound of formula A-6 may be substituted using reductive amination with an appropriately substituted aldehyde or ketone in the presence of a hydride source, such as sodium borohydride or sodium triacetoxyborohydride, provide compounds of formula A-10.

Alternatively, a compound of formula A-3 may be condensed with a dicarbonyl compound of the formula R₃(C═O)₂R₃ and an amine of the formula H₂N—R₅ upon heating in acetic acid to afford a compound of the formula A-4. When compound A-3 is protected with a BOC group, a by-product of formula A-5 may be produced. Compounds of formula A-4 or A-5 may be treated with a hydride source such as lithium aluminum hydride to give certain compounds of formula A-10.

Similarly, a compound of formula A-7 may be coupled to an α-aminoketone as described above for compounds of formula A-1 to yield the corresponding compounds of formula A-8. A compound of formula A-8 may then be cyclized in the presence of an amine of formula H₂N—R₅ or ammonium acetate and subsequently deprotected as described above to arrive at compounds of formula A-10.

Certain compounds of the present invention may be prepared according to the process outlined in Scheme B below.

More specifically, a compound of formula B-1 (wherein the imidazole nitrogen is substituted with R⁵, as defined herein, or R^(5a), a nitrogen protecting group such as SEM, MOM, or the like) may be deprotonated with an organometallic base such as n-butyllithium and then treated with a suitably substituted amide to yield a compound of formula B-2.

Compound B-2 may be brominated to yield a mixture of regioisomers of formula B-3. A compound of formula B-3 may be further elaborated via a reductive amination with an amine of the formula H₂N—R¹ in the presence of a hydride source as described in Scheme A to afford a compound of formula B-4.

The amine of a compound of formula B-4 may be coupled with a suitable carboxylic acid under standard peptide coupling conditions with a coupling agent such as EDCI and an additive such as HOBt to yield compounds of formula B-5.

Certain R³ substituents of the present invention in which a carbon atom is the point of attachment may be introduced into a compound of formula B-5 through a transition metal-catalyzed cross coupling reaction to afford compounds of formula B-6. Suitable palladium catalysts include palladium tetrakis triphenylphosphine and the like. Suitable Lewis acids for the reaction include boronic acids and the like. Compounds protected with R^(5a) may be deprotected under acidic conditions to yield compounds of formula B-7.

In a similar manner, an intermediate B-2 when optionally protected with R^(5a) may be reductively alkylated using methods described above to give a compound of formula B-8, followed by removal of protecting group R^(5a) using conditions described herein to yield a compound of formula B-9.

One skilled in the art will recognize that substituent L (depicted as O in the formulae of Scheme B) may be further elaborated to S or N(R^(d)) of the present invention using conventional, known chemical methods.

Certain compounds of the present invention may be prepared according to the process outlined in Scheme C below.

More specifically, a compound of formula A-10, B-8, or B-9 may be elaborated to a compound of formula C-2 through coupling with a suitable carboxylic acid under standard peptide coupling conditions as described above. One skilled in the art will recognize that substituent L in a compound of formula C-2 (depicted as O) may be converted to S or N(R^(d)) of the present invention using conventional, known chemical methods.

Suitably substituted carboxylic acids of the present invention may either be commercially available or prepared by reported protocols in the scientific literature. Several chemical routes for preparing certain compounds of formula C-1 are outlined below in Schemes D and E.

Specifically, a compound of formula D-1 may be treated with trifluoromethanesulfonic anhydride to afford the triflate compound of formula D-2. A compound of formula D-2 may be converted to a compound of formula D-4 by a variety chemical routes which utilize conventional chemical methods known to those skilled in the art. For example, the bromo group of a compound of formula D-2 may undergo a carboxylation reaction via an initial carbonylation under a carbon monoxide atmosphere in the presence of an appropriate palladium catalyst and DPPF, followed by an aqueous basic workup to afford a compound of formula D-3. Subsequently, the carboxyl group may be converted to a substituent of R^(41a) of formula D-4 using standard peptide coupling conditions. Alternatively, a compound of formula D-4 may be directly prepared via a carbonylation of compound of formula D-2, followed by treatment with HMDS, or a primary or secondary amine.

The compound of formula D-5, known or prepared by known methods, may be treated with EDC in the presence of copper (I) chloride to afford the corresponding alkene of formula D6. A compound of formula D-6 may then undergo a Heck reaction with a compound of formula D-4 in the presence of an appropriate palladium catalyst and phosphino ligand to afford a compound of formula D7. Subsequent hydrogenation of the alkenyl substituent using standard hydrogen reduction methods affords a compound of formula D-8.

Scheme E demonstrates an alternative method for preparing intermediate D-7 of the present invention. A compound of formula E-1 may be elaborated to a compound of formula E-4 using the appropriately adapted synthetic steps described in Scheme D. One skilled in the art will recognize that this transformation may be achieved by manipulation of the reaction sequence. A compound of formula E-4 may be converted to its corresponding nitrile via an aromatic nucleophilic displacement reaction with cyanide anion. One skilled in the art will recognize that a nitrile substituent is a viable synthon for a substituent of R^(41a).

A compound of formula E-4 may participate in a Homer-Wadsworth-Emmons reaction with a compound of formula E-7 in the presence of an organometallic base such as n-butyllithium to afford a compound of formula D-7. This intermediate may be further elaborated as described in Scheme D, herein.

Certain compounds of the present invention may be prepared according to the process outlined in Scheme F below.

More specifically, a compound of formula F-1, wherein R¹¹ is an alkoxycarbonyl as defined above, may be saponified to its corresponding acid, a compound of formula F-2.

A compound of formula F-3 wherein R¹¹ is a cyano substituent may be elaborated to its corresponding aminocarbonyl, compound F-4 by treatment with hydrogen peroxide in the presence of hydroxide anion. Similarly, when R³ is a cyano-substituted aryl ring, it may be treated as described above to form an aminocarbonyl-substituted aryl ring.

Certain substitutents of R¹¹ may be installed via a palladium catalyzed coupling reaction with an X-substituted precursor. For example, a compound of formula F-5 wherein X is iodide, bromide, tosylate, triflate, or the like may be treated with Zn(CN)₂ in the presence of palladium tetrakis triphenylphosphine to give a compound of formula F-6 wherein R¹¹ is cyano.

Treatment of a compound of formula F-5 with Pd(OAc)₂ and a ligand such as 1,1-bis(diphenylphosphino) ferrocene under a carbon monoxide atmosphere provides a compound of formula F-6 wherein R¹¹ is a carboxy substituent.

The palladium catalyzed couplings described above may also be used to install cyano, carboxy, and alkoxycarbonyl substituents onto an aryl ring at R³.

SPECIFIC EXAMPLES

Specific compounds which are representative of this invention were prepared as per the following examples and reaction sequences; the examples and the diagrams depicting the reaction sequences are offered by way of illustration, to aid in the understanding of the invention and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. The instant compounds may also be used as intermediates in subsequent examples to produce additional compounds of the present invention. No attempt has been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.

Reagents were purchased from commercial sources. Nuclear magnetic resonance (NMR) spectra for hydrogen atoms were measured in the indicated solvent with (TMS) as the internal standard on a Bruker Biospin, Inc. DPX-300 (300 MHz) spectrometer. The values are expressed in parts per million down field from TMS. The mass spectra (MS) were determined on a Micromass Platform LC spectrometer or an Agilent LC spectrometer using electrospray techniques. Microwave accelerated reactions were performed using either a CEM Discover or a Personal Chemistry Smith Synthesizer microwave instrument. Stereoisomeric compounds may be characterized as racemic mixtures or as separate diastereomers and enantiomers thereof using X-ray crystallography and other methods known to one skilled in the art. Unless otherwise noted, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. The substituent groups, which vary between examples, are hydrogen unless otherwise noted.

Example 1 2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-isopropyl-N-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-propionamide

A. [1-(2-Oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester

To a solution of commercially available N-α-CBZ-L-alanine (2.11 g, 9.5 mmol) in dichloromethane (50 mL) was added 2-aminoacetophenone hydrochloride (1.62 g, 9.5 mmol). The resulting solution was cooled to 0° C. and N-methylmorpholine (1.15 g, 11 mmol), 1-hydroxybenzotriazole (2.55 g, 18.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.35 g, 12.3 mmol) in that order were added under an Argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous NaHCO₃ solution; the separated organic phase was washed with 2N citric acid, saturated NaHCO₃ solution and brine, then dried over MgSO₄ overnight. After filtration and concentration, the residue was purified by column chromatography on silica gel (eluent, EtOAc:hexane-1:1) to give the pure product: [1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester (2.68 g, 83%). ¹H NMR (300 MHz, CDCl₃): δ 1.46 (3H, d), 4.39 (1H, m), 4.75 (2H, d), 5.13 (2H, d), 5.40 (1H, m), 7.03 (1H, m), 7.36 (5H, m), 7.50 (2H, m), 7.63 (1H, m), 7.97 (2H, m). MS(ES⁺): 341.1 (100%).

B. [1-(4-Phenyl-1H-imidazol-2-yl)-ethyl]-carbamic acid benzyl ester

To a suspension of [1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester (2.60 g, 7.64 mmol) in xylene (60 mL) was added NH₄OAc (10.3 g, 134 mmol) and HOAc (5 mL). The resulting mixture was heated at reflux for 7 h. After being cooled to room temperature, brine was added and the mixture was separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over Na₂SO₄ overnight. After filtration and concentration, the residue was purified by column chromatography on silica gel (eluent, EtOAc:hexane-1:1) to give the title compound (2.33 g, 95%). ¹H NMR (300 MHz, CDCl₃): δ 1.65 (3H, d), 5.06 (1H, m), 5.14 (2H, q), 5.94 (1H, d), 7.32 (10H, m), 7.59 (2H, d). MS(ES⁺): 322.2 (100%).

C. 1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine

To a solution of [1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamic acid benzyl ester (1.5 g, 4.67 mmol) in methanol (25 mL) was added 10% palladium on carbon (0.16 g). The mixture was shaken in a hydrogenation apparatus at rt under a hydrogen atmosphere (10 psi) for 8 h. Filtration followed by evaporation to dryness under reduced pressure gave the crude product 1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.88 g, 100%). ¹H NMR (300 MHz, CDCl₃): δ 1.53 (3H, d), 4.33 (1H, q), 7.23 (3H, m), 7.37 (2H, m), 7.67 (2H, m). MS(ES⁺): 188.1 (38%).

D. Isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine

1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and acetone (0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL), followed by the addition of NaBH(OAc)₃ (0.34 g, 1.61 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with saturated NaHCO₃ solution. The mixture was extracted with EtOAc and the combined extracts were dried over Na₂SO₄. Filtration followed by evaporation to dryness under reduced pressure gave the crude isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.23 g, 100%) which was used for the next reaction without further purification. ¹H NMR (300 MHz, CDCl₃): δ 1.10 (3H, d), 1.18 (3H, d), 1.57 (3H, d), 2.86 (1H, m), 4.32 (1H, m), 7.24 (2H, m), 7.36 (2H, m), 7.69 (2H, m). MS(ES⁺): 230.2 (100%).

E. (2-(4-Hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester

Into a solution of 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid (0.18 g, 0.6 mmol) in DMF (7 mL) was added isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.11 g, 0.5 mmol), 1-hydroxybenzotriazole (0.22 g, 1.6 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.12 g, 0.6 mmol). The resulting mixture was stirred under an Argon atmosphere at it overnight. The reaction mixture was extracted with EtOAc and the combined organic extracts were washed sequentially with saturated aqueous NaHCO₃ solution, 1N HCl, saturated aqueous NaHCO₃ solution, and brine. The organic phase was then dried over MgSO₄, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: EtOAc) to afford the product (2-(4-hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester (0.13 g, 50%). MS(ES⁺): 521.5 (100%).

F. 2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-isopropyl-N-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-propionamide

A solution of (2-(4-hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester (0.13 g, 0.25 mmol) in trifluoroacetic acid (5 mL) was stirred at rt for 2 h. Upon removal of the solvents, the residue was purified by preparative LC and lyophilized to give the TFA salt of the title compound as a white powder (0.042 g). ¹H NMR (300 MHz, CDCl₃): δ 0.48 (3H, d), 1.17 (3H, d), 1.76 (3H, d), 2.28 (6H, s), 3.19 (2H, m), 3.74 (1H, m), 4.70 (1H, m), 4.82 (1H, q), 6.56 (2H, s), 7.45 (4H, m), 7.74 (2H, m). MS(ES⁺): 421.2 (100%).

Example 2 Methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine and Ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine

A. [2-Methyl-1-(2-oxo-2-phenyl-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester

Compound 2a was prepared according to Example 1 using the appropriate reagents, starting materials and methods known to those skilled in the art.

B. [2-Methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]carbamic acid tert-butyl ester

Following the procedure described in Example 1 for the conversion of Compound 1a to Compound 1b, and using the appropriate reagents and methods known to those skilled in the art, [2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]-carbamic acid tert-butyl ester, Cpd 2b, was prepared.

Subsequent to workup, the crude product mixture was subjected to flash silica gel chromatography (eluents: CH₂Cl₂, followed by 4:1 CH₂Cl₂/Et₂O, then EtOAc). Processing of the fractions afforded 1.08 g (27%) of recovered [2-methyl-1-(2-oxo-2-phenyl-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (Cpd 2a), 1.89 g (50%) of [2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]carbamic acid tert-butyl ester (Cpd 2b), and 0.60 g of a mixture of N-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide (Cpd 2c) and acetamide.

Cpd 2c was purified by dissolving it in hot CH₃CN and cooling to 0° C. Collection of the precipitate by suction filtration afforded 0.21 g (7%) of N-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide, Cpd 2c, as a white powder (HPLC: 100% @ 254 nm and 214 nm). ¹H NMR (300 MHz, CDCl₃): δ 7.63 (2H, br s), 7.33 (2H, t, J=7.5 Hz), 7.25-7.18 (2H, m), 4.78 (1H, br s), 2.35 (1H, br m), 2.02 (3H, s), 1.03 (3H, d, J=6.7 Hz), 0.87 (3H, d, J=6.7 Hz); MS (ES⁺) (relative intensity): 258.3 (100) (M+1).

C. Methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]amine

A solution of [2-methyl-1-(4-phenyl-1-H-imidazol-2-yl)-propyl]-carbamic acid tert-butyl ester (0.095 g, 0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing 1.0 M solution of LiAlH₄ in THF (3.0 mL). The reaction was maintained at reflux for 2 h, cooled to room temperature, and quenched by sequential treatment with 0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL of cold water (5° C.). The resultant solid was removed by suction filtration and the filtrate (pH 8-9) was extracted three times with EtOAc. The combined organic fractions were dried over MgSO₄, filtered, and concentrated to afford 0.58 g (84%) of methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine as a light yellow oil (HPLC: 97% @ 254 nm and 214 nm). ¹H NMR (300 MHz, CDCl₃): δ 7.69 (2H, d, J=7.4 Hz), 7.36 (2H, t, J=7.6 Hz), 7.26 (1H, s), 7.25-7.20 (1H, m), 3.62 (1H, d, J=6.3 Hz), 2.35 (3H, s), 2.06 (1H, m), 0.99 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz); MS (ES⁺) (relative intensity): 230.2 (100) (M+1).

D. Ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine

A solution of N-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]acetamide (0.077 g, 0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing 1.0 M solution of LiAlH₄ in THF (3.0 mL). The reaction was maintained at reflux for 11 h, cooled to rt, and quenched by sequential treatment with 0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL of cold water (5° C.). The resultant solid was removed by suction filtration and the filtrate (pH 8-9) was extracted three times with EtOAc. The combined organic fractions were dried over MgSO₄, filtered, and concentrated to afford 0.069 g of a 5:1 mixture (determined by ¹H NMR) of ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine and recovered Cpd 2c as a colorless oil (HPLC: peaks overlap). ¹H NMR (300 MHz, CDCl₃): δ 7.67 (2H, br s), 7.35 (2H, t, J=7.6 Hz), 7.26-7.17 (2H, m), 3.72 (1H, d, J=6.0 Hz), 2.56 (2H, dq, J=13.0, 7.1 Hz), 2.05 (1H, m), 1.08 (3H, t, J=7.1 Hz), 0.97 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz); MS (ES⁺) (relative intensity): 244.2 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification.

Methyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]amine and ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine may be substituted for Cpd 1d of Example 1 and elaborated to compounds of the present invention with the appropriate reagents, starting materials and purification methods known to those skilled in the art.

Example 3 (3,4-Dimethoxy-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine

A solution of 1-(4-phenyl-1H-imidazol-2-yl)-ethylamine (0.061 g, 0.33 mmol) of Example 1, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehyde in 5 mL of anhydrous methanol was stirred at room temperature for 1 h and then cooled to about 0-10° C. in an ice bath for 1 h. The reaction was treated carefully with 0.019 g (0.49 mmol) of sodium borohydride in one portion and maintained at about 0-10° C. for 21 h. Cold 2M aqueous HCl was added dropwise (30 drops), the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The residual material was taken up in EtOAc to yield a suspension that was treated with 5 mL of cold 3M aqueous NaOH and stirred vigorously until clear. The phases were separated and the aqueous layer was extracted three times additional with EtOAc. The combined extracts were dried over MgSO₄, filtered, and concentrated to afford 0.11 g of (3,4-dimethoxy-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine as a light yellow oil (HPLC: 87% @ 254 nm and 66% @ 214 nm). MS (ES⁺) (relative intensity): 338.1 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification. The title compound may be substituted for Cpd 1d of Example 1 and elaborated to compounds of the present invention with the appropriate reagents, starting materials and purification methods known to those skilled in the art.

Example 4 1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethylamine

A. {1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethyl}-carbamic acid tert-butyl ester

A mixture of ammonium acetate (19.3 g, 250 mmol) and glacial HOAc (35 mL) was stirred mechanically and heated to about 100° C. to give a colorless solution in 5-10 min. After cooling to rt, a solid mixture of N-t-BOC-L-Alaninal (commercially available from Aldrich) and 4-fluorophenyl glyoxal hydrate was added in portions while stirring to give a yellow mixture. The resulting mixture was heated at 100° C. for approximately 2 h before cooling to rt. The mixture was cooled to 0-5° C., then basified by dropwise addition of conc. NH₄OH (25 mL), H₂O (25 mL), and EtOAc (40 mL), and additional conc. NH₄OH (50 mL) to render the mixture alkaline. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic phases were filtered through dicalite to remove an orange solid and were washed with saturated aqueous NaCl. The organic phase was then dried over MgSO₄, filtered, and concentrated under reduced pressure to give 4.27 g of an orange-brown residue. The residue was dissolved in a solution of MeCN (22 mL) and DMSO (3 mL) then purified by preparative HPLC on a Kromasil 10u C18 250×50 mm column, eluting with a 35:65 MeCN:H₂O gradient. The pure fractions were combined and lyophilized to give 1.77 g of the product as a yellow-white powder (42%; TFA salt). MS: m/z 306.1 (MH⁺).

B. 1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethylamine

{1-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-ethyl}-carbamic acid tert-butyl ester may be BOC-deprotected using the procedure described in Example 1 for the conversion of Cpd 1e to Cpd 1f. Upon completion of the BOC-deprotection, the resulting amine may be substituted for Cpd 1c of Example 1 and elaborated to compounds of the present invention with the appropriate reagents, starting materials and purification methods known to those skilled in the art.

Example 5 Isopropyl-[4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-amine (mixture of regioisomers)

A. Cpd 5a Regioisomers.

Into a cooled solution of 4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (Tet. Lett. 1986, 27(35), 4095-8) (7.70 g, 28.1 mmol) in dry THF (60 mL) was added n-butyllithium (2.5 M in hexane, 22.5 mL, 56.2 mmol) at −78° C. under N₂. The resulting mixture was stirred at −78° C. for 1 h, followed by the addition of DMF (4.35 mL, 56.2 mmol). After being stirred at −78° C. for an additional hour, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO₃ solution and extracted with EtOAc. The combined organic extracts were dried over Na₂SO₄. After filtration and evaporation, the residue was purified by flash column chromatography (eluent: EtOAc:hexane, 1:9) to give 4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (5.11 g, 60%) as a mixture of regioisomers. ¹H NMR (300 MHz, CDCl₃): δ 0.00 (9H, s), 2.98 (2H, t), 3.62 (2H, t), 5.83 (2H, s), 7.36 (1H, m), 7.44 (2H, m), 7.65 (1H, s), 7.86 (2H, m). MS(ES⁺): 303.0 (42%).

B. Cpd 5b Regioisomers.

Isopropylamine (0.18 g, 3 mmol) and a regioisomeric mixture of 4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (0.91 g, 3 mmol) were mixed in 1,2-dichloroethane (10 mL), followed by addition of sodium triacetoxyborohydride (0.95 g, 4.5 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched with saturated aqueous NaHCO₃ solution. The resultant mixture was extracted with EtOAc and the combined organic phases were dried over Na₂SO₄. After filtration and concentration, the residue was purified by flash column chromatography (eluent: CH₂Cl₂:CH₃OH, 7:3) to give isopropyl-[4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-amine (0.70 g, 68%) as a mixture of regioisomers. ¹H NMR (300 MHz, CDCl₃): δ 0.00 (9H, s), 0.94 (2H, t), 1.11 (6H, d), 2.89 (1H, m), 3.56 (2H, t), 3.94 (2H, s), 5.39 (2H, s), 7.25 (2H, m), 7.37 (2H, m), 7.76 (2H, d). MS(ES⁺): 346.6 (75%).

Compound 5b may be substituted for Cpd 1d of Example 1 and elaborated to compounds of the present invention with the appropriate reagents, starting materials and purification methods known to those skilled in the art.

Example 6 2-Amino-3-(4-hydroxy-phenyl)-N-isopropyl-N-(5-methyl-4-phenyl-1H-imidazol-2-ylmethyl)-propionamide Trifluoroacetate (1:2)

A. Cpd 6a Regioisomers.

Bromine (1.17 mL, 22.76 mmol) was added slowly to an ice cooled regioisomeric mixture of 4(5)-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (5.47 g, 22.76 mmol; JOC, 1986, 51(10), 1891-4) in CHCl₃ (75 mL). The reaction was warmed to rt after 1.5 h, and then was stirred an additional 1 h. The reaction mixture was then extracted with saturated aqueous NaHCO₃, and the organic phase was then dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 7.46 g of crude material. This material was vacuum distilled (bp 127-135° C.; 1 mm Hg) to yield 3.16 g (43%) of a regioisomeric mixture, Cpd 6a, as a yellow liquid, which was used without further purification. ¹H NMR (CDCl₃) δ 0 (s, 9H), 0.9-1.0 (t, 2H), 2.35 (s, 3H), 3.5-3.6 (t, 2H), 5.8 (s, 2H), 9.75 (s, 1H).

B. Cpd 6b Regioisomers.

Isopropyl amine (0.30 g, 5 mmol) in 1,2-dichloroethane (2 mL) was added to a 5° C. solution of regioisomers Cpd 6a (0.96 g, 3 mmol) in 1,2-dichloroethane (70 mL). After stirring for 5 min, sodium triacetoxyborohydride (1.80 g, 8.5 mmol) was added neat to the reaction mixture. The mixture was gradually warmed to rt and stirred for 24 h. At this time, an additional portion of sodium triacetoxyborohydride (0.60 g, 2.8 mmol) was added and the reaction was stirred an additional 16 h. The reaction was then cooled to approximately 10° C. and treated while stirring with saturated aqueous NaHCO₃. After stirring for 15 min, the layers were separated and the organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 1.20 g (T.W. 1.09 g) of a regioisomeric mixture, Cpd 6b, as a yellow oil which was used directly without further purification.

C. Cpd 6c Regioisomers.

Isobutyl chloroformate (0.43 g, 3.15 mmol) was added neat to a 0° C. solution containing 2-tert-butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid (1.21 g, 3.6 mmol; Advanced Chem Tech), N-methylmorpholine (362 μL, 3.3 mmol), and CH₂Cl₂ (60 mL). After stirring 1.5 h, Cpd 6b (1.09 g, 3 mmol) was added to the reaction mixture. The reaction mixture was then warmed to room temperature and stirred for 16 h. The reaction mixture was then adsorbed on silica gel, and flash chromatographed on a silica gel column eluting with 25% ethyl acetate/hexane. The desired fractions were combined and concentrated under reduced pressure to give 715 mg (35%) of regioisomers of Cpd 6c as a clear oil (TLC: 25% EtOAc/hexane R_(f)=0.3, homogeneous; HPLC: 100% at 254 and 214 nm, 7.51 min).

D. Cpd 6d Regioisomers.

To the regioisomers of Cpd 6c (90 mg, 0.132 mmol) in 1,2-dimethoxyethane (2 mL) was added phenyl boronic acid (32.2 mg, 0.26 mmol) followed by 2M Na₂CO₃(aq) (0.53 mL, 1.06 mmol). The resulting mixture was degassed with N₂ for 5 min and then palladium tetrakis triphenylphosphine (53 mg, 0.046 mmol) was added neat. The reaction vessel was capped and warmed to 80° C. for 14 h with rapid stirring. After cooling to room temperature the mixture was dried over MgSO₄, filtered through dicalite, and concentrated under a stream of N₂. The residue was dissolved in a small amount of EtOAc and flash chromatographed on a silica gel column (Eluent: 5%-25% EtOAc/hexane). The desired fractions were concentrated under reduced pressure to yield 55 mg (61%) as regioisomeric mixture of Cpd 6d, which was used without further purification (TLC: 25% EtOAc/hexane R_(f)=0.3; HPLC: 100% at 254 nm; 88% at 214 nm, 6.50 min).

E. 2-Amino-3-(4-hydroxy-phenyl)-N-isopropyl-N-(5-methyl-4-phenyl-1H-imidazol-2-ylmethyl)-propionamide Trifluoroacetate (1:2)

Trifluoroacetic acid (1 mL) was added to the Cpd 6d regioisomers (55 mg, 0.081 mmol) at room temperature. After 6 h, the excess TFA was removed under a stream of N₂. The residue was dissolved in a small amount of acetonitrile and purified by preparative HPLC on a YMC C18 100×20 mm column. The purest fractions were combined and lyophilized to give 37 mg (74%) of the title compound as a white lyophil (TLC: 5:1 CHCl₃:MeOH R_(f)=0.55, homogeneous; HPLC: 100% at 214 nm; HPLC/MS: m/z 393 (MH⁺)). ¹H NMR (MeOH-d₄) δ 0.85-0.9 (d, 3H), 1.2-1.25 (d, 3H), 2.45 (s, 3H), 3.05-3.1 (t, 2H), 4.0-4.15 (m, 1H), 4.55-4.6 (d, 1H), 4.7-4.85 (m, 2H), 6.65-6.7 (d, 2H), 6.95-7.0 (d, 2H), 7.45-7.6 (m, 5H).

Example 7 (3,4-Dichloro-benzyl)-(4-phenyl-1H-imidazol-2-ylmethyl)-amine Trifluoroacetate (1:2)

Using the procedure described in Example 5 and substituting 3,4-dichloro-benzylamine for isopropylamine, (3,4-dichloro-benzyl)-[4(5)-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylmethyl]-amine was prepared as a pair of regioisomers. A sample (95 mg, 0.21 mmol) of this compound was dissolved in TFA (3 mL) at room temperature. After 2 h the mixture was concentrated under a stream of nitrogen. The residue was purified by reverse phase HPLC, the purest fractions were combined and lyophilized to yield desired product (3,4-dichloro-benzyl)-(4-phenyl-1H-imidazol-2-ylmethyl)-amine as an off white lyophil.

Following the procedure described in Example 1, substituting (3,4-dichloro-benzyl)-(4(5)-phenyl-1H-imidazol-2-ylmethyl)-amine for Cpd 1d, compounds of the present invention may be synthesized with the appropriate reagents, starting materials, and purification methods known to those skilled in the art.

Example 8 (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester

A. (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester

Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol; Sources: Chiramer or RSP AminoAcidAnalogues) and N-phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) in dichloromethane (60 mL) was added triethylamine (3.25 mL, 23.3 mmol). The resulting solution was stirred at 0° C. for 1 h and slowly warmed to rt. Upon completion, the reaction was quenched by addition of water. The separated organic phase was washed with 1N NaOH aqueous solution, water and dried over Na₂SO₄ overnight. After filtration and evaporation, the residue was purified by flash column chromatography (eluent: EtOAc-hexane: 3:7) to give the desired product (9.74 g, 99%) as a clear oil; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.06 (2H, d, J=7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m), 5.12 (1H, d, J=8.5 Hz), 6.92 (2H, s); MS (ES+) (relative intensity): 355.8 (100) (M-Boc)⁺.

B. (S)-4-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoic acid

To a suspension of (S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester (9.68 g, 21.3 mmol), K₂CO₃ (14.1 g, 0.102 mol), Pd(OAc)₂ (0.48 g, 2.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.56 g, 4.47 mmol) in DMF (48 mL) was bubbled in gaseous CO for 15 min. The mixture was heated to 60° C. for 8 h with a CO balloon. The cool mixture was partitioned between NaHCO₃ and EtOAc, and filtered. The aqueous layer was separated, acidified with 10% citric acid aqueous solution, extracted with EtOAc, and finally dried over Na₂SO₄. Filtration and concentration of the filtrate resulted in a residue. The residue was recrystallized from EtOAc-hexanes to afford the desired product (7.05 g, 94%); 1H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.42 (6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H, d, J=8.6 Hz), 7.75 (2H, s); MS(ES+) (relative intensity): 251.9 (100) (M-Boc)+.

C. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid methyl ester

Into a stirring solution of (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoic acid (3.00 g, 8.54 mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g, 12.8 mmol) in DMF (36 mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH₄Cl (0.92 g, 17.1 mmol). The resulting mixture was stirred at it for 40 min before being partitioned between aqueous NH₄Cl solution and EtOAc. The separated organic phase was washed sequentially with 2N citric acid aqueous solution, saturated aqueous NaHCO₃ solution, and brine, then dried over Na₂SO₄ overnight. After filtration and concentration, the residue was purified by flash column chromatography (eluent: EtOAc) to give the product. (3.00 g, 100%); ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, br s), 6.09 (1H, br s), 7.46 (2H, s); MS(ES+) (relative intensity): 250.9 (100) (M-Boc)⁺.

D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid

Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0° C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0° C., and extracted with EtOAc, and dried over Na₂SO₄ overnight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); ¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M-Boc)⁺.

Example 9 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A. 2-Methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester

Using the procedures described for Example 3, substituting 5-formyl-2-methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4-dimethoxybenzaldehyde, 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester was prepared.

B. 5-({[2-tert-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e, substituting 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester for Cpd 1d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid of Example 8 for 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 9a was prepared.

C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

5-({[2-tert-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester was dissolved in an ice-chilled (0-10° C.), mixed solvent system of THF (10 mL) and MeOH (5 mL). A LiOH.H₂O/water suspension (2.48 M; 3.77 mL) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3×26 mL). These combined organic phases were dried over MgSO₄, filtered, and concentrated under reduced pressure to give 2.26 g (146% of theory) of pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH₂Cl₂ solution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOH/CH₂Cl₂ system as follows: Initial 100% CH₂Cl₂, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 1.74 g (113% of theory) of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 9b, as a white solid.

D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A portion of Cpd 9b (0.27 g, 0.41 mmol) was dissolved in EtOAc (39 mL)/THF (5 mL), filtered, and subsequently treated with gaseous HCl for 15 min. After completion of the HCl addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214 nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield 0.19 g (71%) of desired Cpd 9c as a white solid di-HCl salt.

Example 10

A. 4-{[1-(4-Phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester

Using the procedure described for Example 3, substituting 4-formyl-benzoic acid methyl ester for 3,4-dimethoxybenzaldehyde, 4-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester was prepared.

B. 4-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phe nyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]amino}-methyl)-benzoic acid methyl ester

4-{[1-(4-phenyl-1H-imidazol-2-yl)ethylamino]-methyl}-benzoic acid methyl ester was substituted for Cpd 1d of Example 1 and elaborated according to the procedure of Example 1 to prepare the product.

C. 4-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]amino}-methyl)-benzoic acid. A solution of

4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoic acid methyl ester (TFA salt), (0.043 g, 0.067 mmol) in 5 mL of THF was cooled in an ice bath. A cold (5-10° C.) 3M aqueous solution of LiOH (5 mL) was added and the reaction mixture was stirred vigorously while cold. Chilled (5-10° C.) 2M aqueous HCl (7.5 mL) was added dropwise to neutralize the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The resultant aqueous suspension was extracted seven times with EtOAc. The extracts were dried over Na₂SO₄, filtered, and concentrated to afford 0.030 g of 4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoic acid as a white powder. The material was taken up in EtOH and treated with 1M HCl in Et₂O. The solution was concentrated and the residue was triturated with CH₃CN. A 0.021 g (53%) sample of 4-({[2-amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzoic acid was collected as its HCl salt. MS (ES⁺) (relative intensity): 513.2 (100) (M+1).

Example 11 3-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzamide

A. 3-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzonitrile

Using the procedure described for Example 3, substituting 3-formyl-benzonitrile for 3,4-dimethoxybenzaldehyde, the product was prepared.

B. [1-{(3-Cyano-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester

3-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzonitrile was substituted for Cpd 1d of Example 1 and elaborated according to the procedure of Example 1 to prepare the product.

C. [1-{(3-Carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester

A solution of [1-{(3-cyano-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.070 g, 0.12 mmol) in 3 mL of EtOH was treated with 1.0 mL of 30% hydrogen peroxide followed immediately by 0.1 mL of a 6M aqueous solution of NaOH. The reaction mixture was stirred vigorously for 18 h and quenched by pouring into chilled (5-10° C.) water. The aqueous solution was extracted five times with Et₂O and the combined extracts were dried over MgSO₄, filtered, and concentrated to provide 0.051 g of [1-{(3-carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester as a colorless residue (HPLC: 84% @ 254 nm and 77% @ 214 nm). MS (ES⁺) (relative intensity): 612.5 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification.

D. 3-({[2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-benzamide

[1-{(3-carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester may be BOC-deprotected using the procedure described in Example 1 for the conversion of Cpd 1e to Cpd 1f to provide the title compound.

Example 12 4-{2-Amino-2-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-3,5-dimethyl-benzamide

A. {1-[2-(2-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester

Compound 2a was prepared according to Example 1 using the appropriate reagents, starting materials and methods known to those skilled in the art.

B. {1-[4-(2-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-carbamic acid tert-butyl ester

Following the procedure described in Example 1 for the conversion of Compound 1a to Compound 1b, and using the appropriate reagents and methods known to those skilled in the art, Cpd 12b, was prepared.

C. 1-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-ethylamine

Using the procedure described for the conversion of Cpd 1e to 1f, Compound 12c was prepared.

D. [1-[{1-[4-(2-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester

Using the procedure described in Example 9, Step D, and substituting 1-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-ethylamine for 1-(4-phenyl-1H-imidazol-2-yl)-ethylamine, the product was prepared.

E. {2-(4-Carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester

To a solution of [1-[{1-[4-(2-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (294 mg; 0.4 mmol) in DMF (2 mL) was added Zn(CN)₂ (28 mg; 0.24 mmol). The resulting mixture was degassed with Argon for 5 min, then Pd(PPh₃)₄ (92 mg; 0.08 mmol) was added neat, and the system was immediately warmed to 100° C. After heating for 6 h, the reaction was cooled to it and partitioned between EtOAc and water. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was subjected to reverse phase HPLC (water/acetonitrile/0.1% TFA). The fractions of interest were combined, basified with saturated aqueous NaHCO₃ and extracted twice with EtOAc. The EtOAc extracts were combined, dried over Na₂SO₄, filtered, and concentrated to afford 146 mg (54%) of desired {2-(4-carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester (HPLC: 96% @ 254 nm and 97% @ 214 nm). This sample was of sufficient quality to use in the next reaction without further purification.

F. 4-{2-Amino-2-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-3,5-dimethyl-benzamide

{2-(4-carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester may be BOC-deprotected using the procedure described in Example 1 for the conversion of Cpd 1e to Cpd 1f to give the title compound.

Example 13 3-(2-{1-[[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoic acid

A. 1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethylamine

Using the procedure described in Example 12, and the appropriately substituted starting materials and reagents, 1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethylamine was prepared.

B. {1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-amine-

Using the procedure described in Example 3, and substituting 1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethylamine for 1-(4-phenyl-1H-imidazol-2-yl)-ethylamine, the product was prepared.

C. [1-[{1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e, substituting {1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-amine for Cpd 1d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid of Example 8 for 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, the product was prepared.

D. 3-(2-{1-[[2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoic acid

To a solution of [1-[{1-[4-(3-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (290 mg; 0.40 mmol) in DMF (5 mL) was added K₂CO₃ (262 mg; 1.9 mmol) and the resulting mixture was degassed with Argon for 5 min. At this time, Pd(OAc)₂ (8.9 mg; 0.04 mmol) and 1,1-bis(diphenylphosphino) ferrocene (46 mg; 0.083 mmol) were added. Carbon monoxide was then bubbled through the resulting mixture for 10 min at rt, the reaction was capped, and warmed to 100° C. for 6 h. After cooling to it the mixture was partitioned between EtOAc and water, filtered through Celite, and then separated. The aqueous phase was then washed with a second portion of EtOAc. The aqueous phase was then acidified to pH 5 with 2N citric acid and the resulting aqueous solution extracted with EtOAc (4×). These latter EtOAc extracts were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product (HPLC: 87% at 254 nm).

E. 3-(2-{1-[[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-di methoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoic acid

3-(2-{1-[[2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-benzoic acid may be BOC-deprotected using the procedure described in Example 1 for the conversion of Cpd 1e to Cpd 1f to give the title compound.

Example 14 4-(2-Amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide

A. [2-Benzyloxy-1-(2-oxo-2-phenyl-ethylcarbamoyl-ethyl]-carbamic acid tert butyl ester

The product was prepared using the procedure described in Example 1 and substituting N-α-BOC-L-serine benzyl ester for N-α-CBZ-L-alanine.

B. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-carbamic acid tert butyl ester

By the procedure described in Example 1 for the conversion of Cpd 1a to Cpd 1b, [2-benzyloxy-1-(2-oxo-2-phenyl-ethylcarbamoyl-ethyl]-carbamic acid tert butyl ester was converted to the product.

C. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethylamine

[2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-carbamic acid tert butyl ester may be BOC-deprotected using the procedure described in Example 1 for the conversion of Cpd 1e to Cpd 1f to give the product.

D. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-isopropylamine

By the procedure described in Example 1 for the conversion of Cpd 1c to Cpd 1 d, [2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethylamine was converted to the product.

E. [1-{[2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-2-(4-ca rbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e, substituting [2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-isopropylamine for Cpd 1d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid of Example 8 for 2-tert-butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, the product was prepared.

F. 4-(2-Amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide (TFA salt)

A solution of [1-{[2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester, (0.287 g, 0.439 mmol), in chloroform (10 mL) was cooled in an ice bath and treated with 0.62 mL (4.4 mmol) of iodotrimethylsilane. The reaction, which immediately clouded, was warmed slowly to room temperature while stirring. After 16 h, the reaction was cooled in an ice bath to 5-10° C. and treated with 100 mL of MeOH. The quenched mixture was stirred at 5-10° C. for 30 min, removed from the ice bath and stirred for an additional 30 min, and concentrated in vacuo to obtain 0.488 g of orange residue that was subjected to reverse phase HPLC (water/acetonitrile/0.1% TFA). The fractions of interest were combined and the sample was lyophilized to afford 0.150 g (59%) of 4-(2-amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide (TFA salt) as a white powder (HPLC: 99% @ 254 nm and 100% @ 214 nm). MS (ES⁺) (relative intensity): 464.1 (100) (M+1).

Example 15 (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid

A. Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester

To a cooled (0° C.) solution of 4-bromo-3,5-dimethylphenol (3.05 g, 15.2 mmol) in pyridine (8 mL) was added trifluoromethanesulfonic anhydride (5.0 g, 17/mmol) dropwise. After completion of addition, the resulting mixture was stirred at 0° C. for 15 min, and then at rt overnight. The reaction was quenched by addition of water, and then extracted with EtOAc. The organic extracts were washed sequentially with water, 2N HCl (2×), brine, and then dried over MgSO₄. Filtration and evaporation to dryness afforded Compound 15b (5.30 g, 95%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 2.45 (6H, s), 7.00 (2H, s).

B. 4-Bromo-3,5-dimethylbenzoic acid

To a solution of Compound 15b (6.57 g, 19.7 mmol) in DMF (65 mL) were added K₂CO₃ (13.1 g, 94.7 mmol), Pd(OAc)₂ (0.44 g, 1.97 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resulting mixture was bubbled in gaseous CO for 10 min and was heated to 60° C. for 7.5 h with a CO_((g)) balloon. The cooled mixture was partitioned between aqueous NaHCO₃ and EtOAc, and filtered. The aqueous phase was separated, acidified with aqueous 6N HCl, extracted with EtOAc, and finally dried over Na₂SO₄. Filtration and concentration of the filtrate resulted in the crude Compound 15c as a brown residue, which was used in the next step without further purification.

C. 4-Bromo-3,5-dimethyl-benzamide

A suspension of Compound 15c in DCM (40 mL) was added SOCl₂ (3.1 mL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal of the solvent by evaporation, the residue was dissolved in DCM (40 mL) and ammonium hydroxide (28% NH₃ in water, 2.8 mL) was added. The mixture was heated at 50° C. for 2 h and concentrated. The residue was diluted with H₂O, extracted with EtOAc, and the organic portion was dried over Na₂SO₄. After filtration and evaporation, the residue was purified by flash column chromatography (eluent: EtOAc) to give the Compound 15d (2.90 g, 65% for 2 steps) as an off-white solid. ¹H NMR (300 MHz, CD₃CN): δ 2.45 (6H, s), 5.94 (1H, br s), 6.71 (1H, br s), 7.57 (2H, s); MS(ES⁺)(relative intensity): 228.0 (100%) (M+1).

Method B:

A mixture of Compound 15b (3.33 g, 10 mmol), PdCl₂ (0.053 g, 0.3 mmol), hexamethyldisilazane (HMDS, 8.4 mL, 40 mmol), and dppp (0.12 g, 0.3 mmol) was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at 80° C. for 4 h. To the reaction mixture was added MeOH (5 mL). The mixture was stirred for 10 min, diluted with 2N H₂SO₄ (200 mL), and then extracted with EtOAc. The EtOAc extract was washed with saturated aqueous NaHCO₃, brine, and then dried over Na₂SO₄. Filtration and evaporation of the resultant filtrate gave a residue, which was purified by flash column chromatography (eluent: EtOAc) to give Compound 15d (1.60 g, 70%) as a white solid.

D. 2-tert-Butoxycarbonylaminoacrylic acid methyl ester

To a suspension of N-Boc-serine methyl ester (Cpd 15e, 2.19 g, 10 mmol) and EDC (2.01 g, 10.5 mmol) in DCM (70 mL) was added CuCl (1.04 g, 10.5 mmol). The reaction mixture was stirred at rt for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO₄. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane˜1:4) to give Compound 15e (1.90 g, 94%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 1.49 (9H, s), 3.83 (3H, s), 5.73 (1H, d, J=1.5 Hz), 6.16 (1H, s), 7.02 (1H, s).

E. (Z)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)acrylic acid methyl ester

A flask charged with Compound 15d (0.46 g, 2.0 mmol), Compound 15f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol), DMF (8 mL) was purged with N_(2 (g)) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 mL, 2.2 mol), the reaction mixture was heated at 110° C. for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1N HCl, saturated aqueous NaHCO₃, brine, and dried over MgSO₄. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane˜1:1 to EtOAc only) to give Compound 15g (0.40 g, 57%) as a white solid. ¹H NMR (300 MHz, CD₃OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1H, s), 7.56 (2H, s); ¹³C NMR (75 MHz, DMSO-d₆): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4, 128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6; MS (ES⁺) (relative intensity): 349.1 (38%)(M+1).

F. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid methyl ester

Into a reactor charged with a solution of Compound 15g (0.56 g, 1.6 mmol) in degassed MeOH (80 mL) was added [Rh(cod)(R,R-DIPAMP)]⁺BF₄ ⁻ under a stream of argon. The reactor was sealed and flushed with H₂, stirred at 60° C. under 1000 psi of H₂ for 14 d. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane˜1:1) to afford Compound 8c (0.54 g, 96%) as a white solid. ee: >99%; ¹H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, br s), 6.09 (1H, br s), 7.46 (2H, s); MS(ES⁺) (relative intensity): 250.9 (100) (M-Boc)⁺.

G. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid

Into an ice-cooled solution of Compound 8c (0.22 g, 0.63 mmol) in THF (3.5 mL) was added an aqueous LiOH solution (1 N, 3.5 mL) and stirred at 0° C. Upon completion of the reaction, the reaction was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCl at 0° C., and extracted with EtOAc. The combined extracts were dried over Na₂SO₄ overnight. Filtration and evaporation of the filtrate to dryness led to Compound 8d (0.20 g, 94%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES⁺) (relative intensity): 236.9 (6) (M-Boc)⁺.

Example 16 Racemic 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid

A. Racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid methyl ester

To a reactor charged with a solution of Compound 15g (0.68 g, 1.95 mmol) in MeOH (80 mL) was added 10% Pd—C(0.5 g). The reactor was connected to a hydrogenator and shaken under 51 psi of H₂ overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness to give Compound 16a (0.676 g, 99%) as a white solid. The ¹H NMR spectrum was identical to that of (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid methyl ester, Compound 8c.

B. Racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid

Using the procedure described for Example 15, for the preparation of (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid, racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid, Compound 16b, was prepared.

Using the procedures of the Examples above and the appropriate reagents, starting materials and purification methods known to those skilled in the art, other compounds of the present invention may be prepared including but not limited to:

TABLE VI Mass Spectral Data for Selected Compounds Theoretical Measured Cpd MW MW (MH⁺) 1 538 539 2 520 521 3 573 574 4 541 542 5 527 528 6 555 556 7 569 570 8 593 594 9 553 554 10 603 604 11 589 590 12 587.2 588.3 13 589.3 590.2 14 569.3 570.2 15 500.2 499.2 16 475.3 476.1 17 583.28 584.5 18 569.26 570.2 19 633.2 634.0 20 599.3 600.2 21 634.3 635.2 22 634.3 635.2 23 598.3 599.2 24 580.3 581.1 25 471.26 472.4 26 633.2 634.0 27 580.3 581.1 28 598.3 599.2 29 599.3 600.0 30 680.3 681.2 31 512.2 513 32 498.3 499.1 33 498.3 499.1 34 528.3 529.2 35 514.3 515.1 36 462.26 463.4 37 482.23 483.4 38 446.27 447.5 39 450.26 451.5 40 530.3 531.2 41 445.3 446.1 42 563.3 564.2 43 504.23 505.3 44 504.23 505.3 45 513.24 514.3 46 492.27 493.2 47 479.25 480.1 48 512.2 513.2 49 540.2 541 50 539.25 540.2 51 553.3 554.1 52 526.3 527.1 53 609.3 610.2 54 458.2 459 55 458.2 459 56 474.3 475.2 57 469.25 470.1 58 543.2 544.3 59 513.3 514.2 60 445.3 446.2 61 456.2 457.1 62 498.2 499.1 63 436.3 437.1 64 601.3 602.2 65 422.1 423.1 66 463.3 464.5 67 491.3 492.1 68 436.3 437.1 69 463.3 464.1 70 454.2 455.0 71 456.2 457.0 72 498.2 499.1 73 463.3 464.2 74 577.3 578.6 75 555.3 555.8 76 513.3 514.2 77 525.3 526.3 78 497.3 498.3 79 525.3 526.2 80 512.2 513.2 81 484.2 485.4 82 438.24 439.2 83 486.24 487.5 84 438.24 439.0 85 463.3 464.2 86 433.2 434.2 87 522.2 523 88 526.3 527.4 89 526.3 527.4 90 511.3 512.4 91 493.2 494.4 92 469.2 470.2 93 469.2 470.4 94 495.3 496.2 95 495.3 496.2 96 498.3 499.2 97 536.2 537.2 98 560.3 561.2 99 518.3 519.2 100 518.3 519.2 101 546.2 547.2 102 528.3 529.2 103 536.2 537.2 104 510.3 511.2 105 544.3 545.3 106 496.3 497.2 107 481.3 482.3 108 523.3 524.8 109 509.3 510.4 110 509.3 510.3 111 509.3 510 112 509.3 510 113 495.3 496.4 114 495.3 496.1 115 496.28 497.4 115 496.28 497.4 116 438.24 439.4 117 438.24 439.4 118 436.2 437.3 119 394.2 395.2 120 525.3 526.2 121 539.3 540.3 122 521.3 522.3 123 464 465 124 421 422 125 450.26 451.5 126 456.23 457.3 127 487.3 488.5 128 487.3 488.6 129 422.2 423.3 130 450 451 131 422.2 423.3 132 394.2 395.2 133 464.2 465.3 134 496.3 497.4 135 450.26 451.37 136 495.3 496.4 137 447.3 448.4 138 526.3 527.4 139 653.4 654.5 140 462.3 463.4 141 488.17 489.16 142 450.26 451.40 143 447.3 448.4 144 419.2 420.3 145 496.28 497.32 146 426.21 427.39 147 454.21 455.22 148 477.3 478 149 488.2 489 150 470.3 471 151 488.2 489 152 398.2 399 153 393 394 154 392 393 155 454.21 455.21 156 470.27 471.36 157 477.2 478.4 158 468.2 469.4 159 496.3 497.4 160 429.2 430.4 161 420.2 421.4 162 448.3 449.4 163 438.24 439.1 164 556.23 557.1 165 434.27 435.1 166 420.25 421.1 167 449.3 450.2 168 433.3 434.2 169 415.2 416.2 170 434.3 435.3 171 392.2 393.3 172 497.2 498.3 173 479.2 480.3 174 434.3 435.3 175 484.2 485.2 176 420.2 421.4 177 454.2 455.3 178 433.3 434.1 179 489.3 490.1 180 489.3 489.9 181 447.3 448.1 182 447.3 448.3 183 433.3 434.2 184 433.3 434.2 185 405.2 406.2 186 387.2 388.2 187 406.2 407.2 188 378.2 379.2 189 427.2 428 190 446.3 447.4 191 418.2 419.4 192 418.2 419.3 193 390.2 391.3 194 406.2 407.5 195 378.2 379.3 196 419.2 420.4 197 433.3 434.1 198 350.2 351.1 199 378.2 379.2 202 391.2 392 203 391.2 391.9 204 378.2 379 205 406.2 407 206 392.2 393.3 207 392.2 393.2 208 378.2 379.3 209 378.2 379.2 210 364.2 365.2 211 364.2 365.2 212 350.2 351.2 213 350.2 351.1 214 378.2 379.1 215 378.2 379.1 216 406.2 407.2 217 406.2 407.1 218 468.3 469.4 219 440.2 441.3 220 468.3 469.4 221 440.2 441.2 222 392.2 393.2 223 420.3 421.2 224 420.3 421.1 225 392.2 393.2 226 539 540 227 539 540 228 587 588 229 633 634 230 599.3 599.8 231 512.2 513.2 239 617.2 618.2 242 563.3 564.2 246 519.3 520.0 247 548.3 549.2 248 552.2 553.2 249 536.2 537.0 250 526.3 527.2 251 512.3 513.2 252 554.3 555.3 253 540.2 541.2 254 540.2 541.2 255 554.3 555.3 256 529.2 530.2 257 543.2 543.9 260 542.2 543.2 261 514.2 515.1 262 528.2 529.1 266 512.2 513.2 267 535.2 536.0 268 556.3 557.2 269 525.2 526.0 270 511.2 512.2 271 539.2 540.2 272 525.2 526.0 273 541.2 542.4 274 618.3 619.2 275 589.2 590.2 276 559.2 560.2 277 559.2 560.2 278 617.2 618.2 279 528.2 528.9 280 583.3 584.4 281 555.2 556.2 282 569.3 570.2 283 541.2 542.2 284 555.2 556.3 285 541.2 542.4 286 516.2 517.0 287 502.2 503.1 288 648.6 648.0 289 695.2 695.7 290 648.6 648.0 291 648.6 648.0 292 526.3 527.4 293 562.2 563.2 294 562.2 563.2 295 568.3 569.3 296 638.3 638.8 297 513.2 513.7 298 583.3 583.8 299 612.3 613.3 300 608.3 609.3 301 644.3 644.7 303 515.2 515.8 304 501.2 502.2 305 617.3 617.8 306 661.3 661.8 307 566.3 566.8 308 661.3 661.8 309 649.3 650.0 310 641.3 642.3 311 554.3 555.3 312 554.3 555.3 313 554.3 555.3 314 554.3 555.3 315 627.3 628.3 316 540.2 541.3 317 540.2 541.3 318 589.2 590.2

BIOLOGICAL EXAMPLES

Opioid receptor binding affinity of the compounds of the present invention was determined according to the following procedures and the indicated results were obtained.

Example 1 Rat Brain Delta Opioid Receptor Binding Assay

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) are killed by cervical dislocation, and their brains removed and placed immediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrains are separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains are homogenized in Tris buffer in a Teflon® glass homogenizer. The homogenate is diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet is resuspended in the same volume of Tris buffer containing 5 mM MgCl₂ with several brief pulses from a Polytron homogenizer. This particulate preparation is used for the delta opioid binding assays. Following incubation with the delta selective peptide ligand ˜4 nM [³H]DPDPE at 25° C. for 2.5 h in a 96-well plate with total volume of 1 mL, the plate contents are filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters are rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a microwave oven 2 min twice. To each sample area 2×50 μL of Betaplate Scint scintillation fluid (LKB) is added and analyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.

The data are used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound is evaluated) or a K_(i) value (when a range of concentrations is tested). % inhibition is calculated as: [(total dpm−test compound dpm)/(total dpm−nonspecific dpm)]*100. Kd and Ki values were calculated using GraphPad PRISM data analysis program. The biological activity of the compounds of the present invention is shown in Table VII.

Example 1a Rat Brain Delta Opioid Receptor Binding Assay-Version 1a

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) were killed by cervical dislocation, and their brains removed and placed immediately in ice-cold Tris HCl buffer (50 mM, pH 7.4). The forebrains were separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains were homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet was resuspended in the same volume of Tris buffer containing 5 mM MgCl₂ with several brief pulses from a Polytron homogenizer. This particulate preparation was used for the delta opioid binding assay. Following incubation with 0.1 nM of the delta selective ligand [³H]naltrindole at 25° C. for 2.5 h in a 96-well plate with total 1 mL, the plate contents were filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters were rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a microwave oven. To each sample area, Betaplate Scint scintillation fluid (LKB) was added and the resulting radioactivity quantified on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter. Kd and Ki values were calculated using the GraphPad PRISM data analysis program. The biological activity of the compounds of the present invention is shown in Table VII.

Example 2 Rat Brain Mu Opioid Receptor Binding Assay

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) are killed by cervical dislocation, and their brains removed and placed immediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrains are separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains are homogenized in Tris buffer in a Teflon® glass homogenizer. The homogenate is diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet is resuspended in the same volume of Tris buffer containing 5 mM MgCl₂ with several brief pulses from a Polytron homogenizer. This particulate preparation is used for the mu-opioid binding assays. Following incubation with the mu selective peptide ligand .about.0.8 nM [³H]DAMGO at 25° C. for 2.5 h in a 96-well plate with total 1 mL, the plate contents are filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters are rinsed three times with 2 mL of 10 mM HEPES (pH7.4), and dried in a microwave oven 2 min twice. To each sample area 2×50 μL of Betaplate Scint scintillation fluid (LKB) is added and analyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.

The data are used to calculate either the % inhibition compared to control binding (when only a single concentration of test compound is evaluated) or a K_(i) value (when a range of concentrations is tested). % inhibition is calculated as: [(total dpm−test compound dpm)/(total dpm−nonspecific dpm)]*100. Kd and Ki values were calculated using GraphPad PRISM data analysis program. The biological activity of the compounds of the present invention is shown in Table VII.

Example 2a Rat Brain Mu Opioid Receptor Binding Assay-Version 2a

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) were killed by cervical dislocation, and their brains removed and placed immediately in ice-cold Tris HCl buffer (50 mM, pH 7.4). The forebrains were separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains were homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue per 80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet was resuspended in the same volume of Tris buffer containing 5 mM MgCl₂ with several brief pulses from a Polytron homogenizer. This particulate preparation was used for the mu opioid binding assay. Following incubation with 0.8 nM of the mu selective ligand [³H]DAMGO at 25° C. for 2.5 h in a 96-well plate with total 1 mL, the plate contents were filtered through Wallac filtermat B sheets on a Tomtec 96-well harvester. The filters were rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a microwave oven. To each sample area, Betaplate Scint scintillation fluid (LKB) was added and the resulting radioactivity quantified on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter. Kd and Ki values were calculated using the GraphPad PRISM data analysis program.

TABLE VII r Ki δ * r Ki δ * Ver. 1a r Ki μ * Cpd (nM) (nM) (nM) 1 13.2 1.1 2 3 4 11, 17 2.41 5 630, 183 1.19 6 1.7 7 8 0.43, 0.15 0.51 9 0.11 0.16 10 11 0.54 0.23 12 0.08 13 14 0.36 15 16 17 60 0.22 18 0.38-14.4 0.75, 1.1 19 20 21 22 23 24 25 26 27 28 29 28 25 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 0.24 0.14 49 50 0.58 1.68 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 0.66 0.51 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 12 0.26 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 4.51 0.03 164 120 0.38 165 23.6 0.07 166 5.58, 12.03 0.03, 0.07 167 10000 3.15 168 8867 5322 169 10000 853 170 32.6 0.48 171 10000 141 172 10000 150 173 5069 45.7 174 175 166 3.60 176 10000 156 177 255 13.4 178 104 0.6 179 10000 7116 180 5221 1209 181 341 1.3 182 1859 7 183 604 4 184 10000 19.5 185 182 6716 186 515 5314 187 5198 121 188 541 307 189 360 277 190 13.8 2.61 191 727.3 189 192 7.64 0.09 193 182.1 21.1 194 14.8 0.06 195 306.2 9.29 196 197 4.27 0.9 198 5178 152 199 26.3 0.3 202 31.5 5.9 203 49.3 29.1 204 205 4.44 0.14 206 5.8 0.2 207 5.3, 5.37, 0.05, 0.08, 14.7 0.1 208 33 1.3 209 708 17 210 1862 420.3 211 180 5.9 212 1278 103 213 5658 1263 214 308 44 215 126 0.43 216 1.14 0.04 217 5.4 1.08 218 1.45 0.03 219 87.83 0.87 220 6921 157.2 221 9.58 0.36 222 394 91.2 223 2.6 0.87 224 1.41 0.03 225 112 0.73 226 48 227 0.08, 0.46 0.96 228 27.8 0.35 229 230 10 5 231 1070 6.19 239 0.1 0.44 242 0.18 0.59 246 0.035 0.15 247 0.4 0.61 248 0.44 0.11 249 0.18 0.12 250 0.21 0.06 249 0.18 0.12 250 0.21 0.06 251 0.26 0.08 249 0.18 0.12 250 0.21 0.06 251 0.26 0.08 256 3.82 7.08 257 14.0 1.22 260 0.13 0.24 261 8.01 0.79 262 17.5 1.1 266 267 0.46 1.53 268 269 0.61 6.24 0.37 270 1.03 4.47 1.37 271 12.2 0.27 272 15.6 1.1 273 1140 754 274 275 0.47 0.69 276 115 47 277 0.14 0.44 278 49 12 279 5.2 0.137 280 32 3 281 721 399 282 907 185 283 6735 3572 284 1526 1033 285 2897 1868 286 0.11 0.05 287 0.14 0.13 288 0.17 0.43 288 0.17 0.43 289 0.1, 3.8 0.25 290 0.69 0.43 291 0.12 0.47 292 100 0.65 293 3175 646 295 3.95 0.18 296 2.2 0.49 297 44 0.11 298 44 0.3 299 1.16 0.44 300 0.29 0.09 301 0.76 0.09 303 24.5 3.87 304 119 161 305 1.24 0.2 306 0.18 0.9 307 0.07 0.4 308 0.48 1.2 318 1220 357 * The binding assays described above may be associated with a margin of error between 10-20%.

Example 3 Human Mu Opioid Receptor Binding Assay

Membranes from Chinese Hamster Ovary cells expressing the human p opioid receptor (Perkin Elmer #RBHOMM400UA) are homogenized in assay buffer (50 mM Tris, pH 7.5 with 5 mM MgCl₂) using a glass tissue grinder, Teflon pestle and a Steadfast Stirrer (Fisher Scientific). The concentration of membranes is adjusted to 300 μg/mL in assay buffer and 100 μL is dispensed into each well of the assay plate, a 96 well round bottom polypropylene plate. Compounds to be tested are solubilized in DMSO (Pierce), 10 mM, then diluted in assay buffer to 6× the desired final concentration. The ligand, ³H-Damgo (Perkin Elmer #NET-902) is also diluted in assay buffer to 3.6 nM. In a second 96 well round bottom polypropylene plate, known as the premix plate, 60 μL of the 6× compound is combined with 60 μL of 3.6 nM ³H-Damgo. From this premix plate 50 μL is transferred to the assay plate containing the membranes, in duplicate. The assay plate is incubated for 2 h at room temperature. A GF/C 96 well filter plate (Perkin Elmer #6005174) is pretreated with 0.3% polyethylenimine for 30 min. The contents of the assay plate are filtered through the filter plate using a Packard Filtermate Harvester, and washed 3 times with 0.9% saline that is 4° C. The filter plate is dried, the underside sealed, and 30 μL Microscint20 (Packard #6013621) added to each well. A Topcount-NXT Microplate Scintillation Counter (Packard) is used to measure emitted energies in the range of 2.9 to 35 KeV. Results are compared to maximum binding, wells receiving no inhibitors. Nonspecific binding is determined in the presence of 1 μM unlabelled Damgo (Tocris #1171). The biological activity of the compounds of the present invention is shown in Table VIII.

The biological activity of the compounds of the present invention may also be measured in a human delta opioid receptor binding assay using the following example.

Example 4 Human Delta Opioid Receptor Binding Assay

This assay is designed to test the ability of a compound to interfere with the binding of tritiated Naltrindole to the human delta subtype 2 opioid receptor. Membranes from Chinese Hamster Ovary cells expressing the human delta subtype 2 opioid receptor (Perkin Elmer #RBHODM400UA) are homogenized in assay buffer (50 mM Tris, pH 7.5 with 5 mM MgCl₂) using a glass tissue grinder, Teflon pestle and a Steadfast Stirrer (Fisher Scientific). The concentration of membranes is adjusted to 100 μg/mL in assay buffer and 100 μL is dispensed into each well of the assay plate, a 96 well round bottom polypropylene plate. Compounds to be tested are solubilized in DMSO (Pierce), 10 mM, then diluted in assay buffer to 6× the desired final concentration. The ligand, ³H-Naltrindole (Perkin Elmer #NET-1065) is also diluted in assay buffer to 6 nM. In a second 96 well round bottom polypropylene plate, known as the premix plate, 60 μL of the 6× compound is combined with 60 μL of 6 nM ³H-Naltrindole. From this premix plate 50 μL is transferred to the assay plate containing the membranes, in duplicate. The assay plate is incubated for 30 min at room temperature. A GF/C 96 well filter plate (Perkin Elmer #6005174) is pretreated with 0.3% polyethylenimine for 30 min. The contents of the assay plate are filtered through the filter plate using a Packard Filtermate Harvester, and washed 3 times with 0.9% saline that is 4° C. The filter plate is dried, the underside sealed, and 30 μL Microscint20 (Packard #6013621) added to each well. A Topcount-NXT Microplate Scintillation Counter (Packard) is used to measure emitted energies in the range of 2.9 to 35 KeV. Results are compared to maximum binding, wells receiving no inhibitors. Nonspecific binding is determined in the presence of 1 μM unlabelled Naltrindole (Sigma #N115).

Biological activity measured for select compounds of the present invention are listed in Table VIII below, including δ- and μ-opioid receptor binding (K_(i)), as determined using the procedures outlined above.

TABLE VIII hKi δ * hKi μ * Cpd (nM) (nM) 1 3.6 2 2.9 3 13 4 5.5 5 3.9 6 2 7 6.8 8 2.5, 4.4 9 10.9 10 15.5 11 5.1 12 4.1 13 4.8 14 4.7 15 285 16 16 17 2.2 18 1.7 19 18.2 20 63 21 37.6 22 ~200 23 34.3 24 9.3 26 17 27 30 28 44 29 38 30 34 31 19 32 6.8 33 6.9 34 19 35 2.8 36 5.6 37 183 38 19 39 0.9 40 152 41 1.6 42 5.8 43 6.9 44 8.7 45 1.2 46 35 47 22 48 0.4 49 48 50 1.4 51 113 2.7 52 66 12.1 53 96 13.1 54 172 1.1 55 44 1.8 56 225 65.3 57 2.2 0.66 58 70 8.5 59 120 5.1 60 114 2 61 243 3 62 69 2.4 63 473 58 64 1108 117 65 517 0.36 66 550 6.5 67 438 4.5 68 59 0.6 69 272 4.4 70 85 2.6 71 102 0.57 72 71 1.03 73 151 1.9 74 63 9.8 75 8.5 2.6 76 43.1 1.6 77 13.5 1.8 78 28.9 2.4 79 11.5 1.7 80 0.95 1.09 81 15.7 1.7 82 46 2.39 83 48 4.67 84 9.6 1.1 85 1175 5.4 86 400 1 87 38.9 12.6 88 16.2 5.8 89 19.3 9.2 90 6.6 0.7 91 15 4.8 92 5.4 0.25 93 9.5 0.9 94 403 4.1 95 278 7.8 96 14.6 9.7 97 6.3 19.2 98 54 48 99 19.3 16 100 88 20 101 47 24 102 5.2 3.5 103 9.7 23 104 484 100 105 742 410 106 279 150 107 584 2.95 108 43.3 23.5 109 77 8.2 110 1402 191 111 307 6.4 112 135 9.5 113 16 114 49 1.39 115 321 68 116 30.3 0.54 117 118 0.24 118 316, 1.04 212 119 >10,000 185 120 740 20.8 121 182 25.3 122 107 12.8 123 84 47 124 1279 1.7 125 237 8.6 126 164 7.8 127 710 47 128 58 129 25.3 130 712 1.6 131 675 3.1 132 166 133 108 11.5 134 463 121 135 1040 7 136 1607 726 137 445 138 1183 104 139 1263 58 140 985 79 141 252 52 142 454 8.2 143 69 1.6 144 251 1.3 145 267 146 71 147 241 149 408 150 992 151 1295 152 >10,000 153 >10,000 154 >10,000 1 155 345 156 380 0.59 157 >10,000 2.2 158 >10,000 0.23 159 400 8.6 160 >10000 >1000 161 >10000 >1000 162 173 7.6 163 301, 63 0.67 164 16.3 165 322 0.45 166 300, 0.39, 0.5 375 167 4.2 190 285 191 >10,000 192 0.62 193 >10,000 194 103 0.13 195 >10,000 9.8 196 197 198 >10,000 140 199 209 0.29 203 501 13.7 204 7.7 205 206 275.4 207 132.2 208 1.2 209 23 210 0.29 211 212 55 213 >1000 214 29 215 1.5 216 217 506 218 189 3.92 219 16.2 220 377 221 0.42 222 185 223 224 81.3 0.65 225 1.4 226 7.91 227 1.92 228 15.9 229 12 231 28 239 242 2.35 246 5.63 256 2 257 3.4 260 0.58 261 2.58, 1.3 262 3.24 266 69 267 6.88 268 5.79 269 21.5 270 3.27 271 15.5 272 1.93 273 325 274 >1000 289 2.2 303 3.8 304 41

Example 5 Delta Opioid Receptor Functional Assay: [³⁵S]GTPγS Binding Assay in CHO-hδ Cell Membranes, Version 1 Preparation of Membranes

CHO-hδ cell membranes were purchased from Receptor Biology, Inc. (Baltimore, Md.). 10 mg/ml of membrane protein suspended in 10 mM TRIS-HC pH 7.2, 2 mM EDTA, 10% sucrose.

Membranes were maintained at 4-8° C. A portion (1 ml) of membranes was added into 15 mL cold binding assay buffer. The assay buffer contained 50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membrane suspension was homogenized with a Polytron for 2 times and centrifuged at 3000 rpm for 10 min. The supernent was then centrifuged at 18,000 rpm for 20 min. The pellet was saved in a tube and 10 ml assay buffer was added into the tube. The pellet and buffer were mixed with a Polytron.

Incubation Procedure

The pellet membranes (20 μg/ml) were preincubated with SPA (10 mg/ml) at 25° C. for 45 min in the assay buffer. The SPA (5 mg/ml) coupled with membranes (10 μg/ml) was then incubated with 0.5 nM [³⁵S]GTPγS in the same HEPES buffer containing 50 μM GDP in total volume of 200 μl. Increasing concentrations of receptor agonists were used to stimulate [³⁵S]GTPγS binding. The basal binding was tested in the absent agonists and no specific binding was tested in the present 10 μM unlabeled GTPγS. The data were analyzed on a Top counter.

Data

The % of Basal=(stimulate−non specific)*100/(basal−non specific). EC50 values were calculated using a Prism program.

Example 6 Delta Opioid Receptor Functional Assay: [³⁵S]GTPγS Binding Assay in NG108-15 Cell Membranes, Version 2 Preparation of Membranes

NG108-15 cell membranes were purchased from Applied Cell Sciences (Rockville, Md.). 8 mg/ml of membrane protein suspended in 10 mM TRIS-HC pH 7.2, 2 mM EDTA, 10% sucrose.

Membranes were maintained at 4-8° C. A portion (1 ml) of membranes was added into 10 ml cold binding assay buffer. The assay buffer contained 50 mM Tris, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EGTA. The membrane suspension was homogenized with a Polytron for 2 times and centrifuged at 3000 rpm for 10 min. The supernent was then centrifuged at 18,000 rpm for 20 min. The pellet was saved in a tube and 10 ml assay buffer was added into the tube. The pellet and buffer were mixed with a Polytron.

Incubation Procedure

The pellet membranes (75 μg/ml) were preincubated with SPA (10 mg/ml) at 25° C. for 45 min in the assay buffer. The SPA (5 mg/ml) coupled with membranes (37.5 μg/ml) was then incubated with 0.1 nM [³⁵S] GTPγS in the same Tris buffer containing 100 μM GDP in total volume of 200 μl. Increasing concentrations of receptor agonists were used to stimulate [³⁵S] GTPγS binding. The basal binding was tested in the absent agonists and no specific binding was tested in the present 10 μM unlabeled GTPγS. The data were analyzed on a Top counter.

Data Analysis

The following parameters were calculated:

${\% \mspace{14mu} {Stimulation}} = {\frac{\left( {{{test}\mspace{14mu} {compound}\mspace{14mu} {cpm}} - {{non}\text{-}{specific}\mspace{14mu} {cpm}}} \right)}{\left( {{{Basal}\mspace{14mu} {cpm}} - {{non}\text{-}{specific}\mspace{14mu} {cpm}}} \right)} \times 100.}$ %  Inhibition = (%  stimulation  by  1  µM  SNC 80 − %  stimulation  by  1  µM  SNC 80  in  presence   of  test  compound) × 100/(%  Stimulation  by  1  µM  SNC 80 − 100) %  Basal = (stimulate − non  specific) * 100/(basal − non  specific).EC₅₀  values   were  calculated  using  GraphPad  Prism.

Example 7 Mu Opioid Receptor Functional Assay: [³⁵S]GTPγS Binding Assays in CHO-hMOR Cell Membranes, Versions 1 and 2

CHO-hMOR cell membranes were purchased from Receptor Biology, Inc. (Baltimore, Md.). About 10 mg/ml of membrane protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose, and the suspension kept on ice. One ml of membranes was added to 15 ml cold binding assay buffer containing 50 mM HEPES, pH 7.6, 5 mM MgCl₂, 100 mM NaCl, 1 mM DTT and 1 mM EDTA. The membrane suspension was homogenized with a Polytron and centrifuged at 3,000 rpm for 10 min. The supernatant was then centrifuged at 18,000 rpm for 20 min. The pellet was resuspended in 10 ml assay buffer with a Polytron.

The membranes were preincubated with wheat germ agglutinin coated SPA beads (Amersham) at 25° C. for 45 min in the assay buffer. The SPA bead (5 mg/ml) coupled membranes (10 μg/ml) were then incubated with 0.5 nM [³⁵S]GTPγS in the assay buffer. The basal binding is that taking place in the absence of added test compound; this unmodulated binding is considered as 100%, with agonist stimulated binding rising to levels significantly above this value. A range of concentrations of receptor agonists was used to stimulate [³⁵S]GTPγS binding. Both basal and non-specific binding was tested in the absence of agonist; non-specific binding determination included 10 μM unlabeled GTPγS.

Compounds were tested for function as antagonists by evaluating their potential to inhibit agonist-stimulated GTPγS binding. Radioactivity was quantified on a Packard TopCount. The following parameters were calculated:

${\% \mspace{14mu} {Stimulation}} = {\frac{\left( {{{test}\mspace{14mu} {compound}\mspace{14mu} {cpm}} - {{non}\text{-}{specific}\mspace{14mu} {cpm}}} \right)}{\left( {{{Basal}\mspace{14mu} {cpm}} - {{non}\text{-}{specific}\mspace{14mu} {cpm}}} \right)} \times 100.}$ %  Inhibition = (%  stimulation  by  1  µM  SNC 80 − %  stimulation  by  1  µM  SNC 80  in  presence   of  test  compound) × 100/(%  Stimulation  by  1  µM  SNC 80 − 100) EC₅₀  values   were  calculated  using  GraphPad  Prism.

Biological activity measured for select compounds of the present invention are listed in Table VIII below, including δ- and μ-opioid receptor functional data (% I and EC50), as determined from a single set of experiments using the procedures outlined above.

TABLE IX DOR GTP- DOR GTP- DOR GTP- MOR GTP MOR GTP MOR GTP binding binding binding binding binding MOR GTP binding Cpd Assay_v1 Assay_v2_ Assay v2 assay v2 assay_v2 assay_v1% assay_v1 No. EC50 (nM) EC50 (nM) (% I) EC50 (nM) (% I) of Basal (% I) 1 88 22.10 4 46 66.12 5 >10,000 47.12 71 7.87 8 >10,000 94.03 1.2 13.95 9 3.4 67.13 14 0.6 59.70 17 1.3 68.64 2.5 8.71 18 >10,000 100 18 1.0 7.54 20 >10,000 78.74 29 >10,000 79.05 48 >10,000 108.36 2.2 24.53 50 1.4 60.27 51 27 66.04 75 1.4 65.35 114 35 717.59 13.20 117 37 816.16 3.31 122 278.08 41.93 130 16 866.39 1.62 131 99 391.98 28.64 146 27 740.77 2.79 147 51 779.35 1.00 149 44 753.53 1.00 150 49 476.63 53.35 151 350 606.38 24.19 155 150 655.93 14.32 163 21 1286.00 1.00 164 2500 1077.00 1.00 165 231 1182.00 1.00 166 21 1448.00 1.00 166 71 1425.00 1.00 167 780.00 17.00 170 115 1031.00 26.00 173 147.00 85.00 174 20 864.00 42.00 175 471.00 53.00 177 625.00 23.00 178 1059.00 10.00 181 1304.00 1.00 182 1091.00 6.00 183 2320 962.00 27.00 184 862.00 13.00 190 3830 109, 194 70.00 192 76 383.00 30.00 193 182.00 54.00 194 189 558.00 1.00 195 378.00 34.00 196 24 620.00 1.00 197 140 582.00 1.00 199 217 465.00 11.00 202 1580 529.00 1.00 203 515 331.00 20.00 205 32 566.00 1.00 206 37 446.00 1.00 207 8.65 432, 1160 40.00 207 12 1183.00 21.00 208 475.00 1.00 209 295.00 10.00 210 414.00 10.00 211 371.00 10.00 214 26000 295.00 3.00 215 1060 606.00 1.00 216 16 666.00 1.00 217 82 599.00 1.00 218 20 599.00 1.00 219 3560 611.00 1.00 221 308 427.00 13.00 223 56 495.00 1.00 224 103 694.00 1.00 225 2190 657.00 1.00 226 >10,000 19.71 227 >10,000 66.56 60.8 36.00 230 48.93 239 >10,000 242 >10,000 91.45 246 0.3 47.01 4.5 21.30 247 44 41.89 248 15 31.72 249 8 20.14 250 10 34.93 251 18 53.94 252 32.1 66.00 4.15 24.00 253 1.35 52.00 251 28.00 254 6.27 62.00 316 42.00 255 13.1 54.00 3.48 33.00 256 >10,000 89.19 13 29.40 257 7.4 48.88 3.9 10.96 260 >10,000 100.97 1.5 2.89 261 21 30.04 17 5.88 267 6 31.76 269 86 21.18 48 1.00 270 1000 63.51 56 6.61 275 3 72.08 286 2.6 34.65 287 >10,000 84.50 288 >10,000 74.54 289 >10,000 86.27 290 >10,000 52.41 291 >10,000 96.52 295 2.2 71.66 1.4 8.21 296 7.9 69.41 2.2 9.35 299 2.3 1.0 12.11 300 32 2.6 15.40 301 >10,000 109.56 2.6 76.20 303 95 23.85 30 1.00 309 23.0 47.00 310 3920 51.00 311 1.02 41.00 312 58.7 35.00 313 5.03 49 50.6 29.00 316 24.1 76

Example 8 In Vivo Assay-Stress-Induced Fecal Output (Fecal Output for I Hr)

This assay evaluates the fecal output in novel environment-stressed mice to that of acclimated controls.

Methods: Adult, male, Crl:CD-1(ICR) mice, weighing ˜30-35 g were used in these studies, with a minimum of 10 mice per dose group. One group of mice was assigned as acclimated, or “non-stressed” controls. These control mice were transported from colony housing, where they were housed 3/cage in polycarbonate cages with access to food and water ad lib. to the procedure room. The mice were removed from their home cages and individually housed in 20 cm wide×20 cm deep×15 cm tall cages, equipped with a wire mesh bottom where they remained for a 16-18 hr period of acclimation to their novel environment. Mice were allowed access to food and water ad lib. during acclimation. The other groups of mice were assigned as non-acclimated, or “stressed” treatment groups. Each mouse in each group was weighed and vehicle, or test compound, was intragastrically administered by oral intubation in 0.5% methylcellulose. Mice were allowed access to water only ad lib. during the test period. After compound administrations, acclimated (control) as well as non-acclimated (stressed) mice were individually housed in a 20 cm wide×20 cm deep×15 cm tall cage, with a wire mesh bottom. An absorbent cardboard is placed beneath the cages. The number of fecal pellets excreted by each mouse was determined at hourly intervals following placement of the mice in the individual cages. Raw Data=# of fecal pellets/mouse/hr. The mean fecal pellet output for each test group was calculated and the results expressed as a percent of the mean fecal pellet output of the control group (the acclimated, non-stressed group, to which vehicle only was administered). ANOVA was performed and Tukey's Multiple Comparison Test used to compare the means, which were considered significantly different when P<0.05. Data is shown in Table X, XI, and XII.

TABLE X Fecal Output (# pellets) Cpd dose NES % cpd % cpd % No. (mg/kg) control NES cpd ctrl control NES 18 30 2.3 3.8 3.1 166.7 137.8 82.7 50 30 2.3 7.0 3.3 304.3 143.5 47.1 55 30 3.9 14.1 8.3 361.5 212.8 58.9 57 30 3.9 14.1 7.6 361.5 194.9 53.9 58 30 2.3 7.0 3.9 304.3 169.6 55.7 75 30 3.1 9.1 6.4 293.5 206.5 70.3 75 30 1.9 3.9 1.4 206.7 73.3 35.5 78 30 3.6 7.3 3.3 202.8 91.7 45.2 79 30 3.6 7.3 7.1 202.8 197.2 97.3 80 30 3.6 7.3 5.5 202.8 152.8 75.3 80 30 3.9 13.1 10.3 335.9 264.1 78.6 85 30 5.4 12.0 7.9 222.2 146.3 65.8 87 30 7.3 12.9 10.3 176.7 141.1 79.8 89 30 5.0 11.6 6.4 232.0 128.0 55.2 90 30 3.1 12.9 10.3 416.1 332.3 79.8 91 30 3.1 12.9 8.9 416.1 287.1 69.0 92 30 3.6 11.1 9.2 308.3 255.6 82.9 93 30 3.6 11.1 5.0 308.3 138.9 45.0 94 30 2.7 9.1 9.4 337.0 348.1 103.3 95 30 2.7 9.1 8.5 337.0 314.8 93.4 97 30 7.3 12.9 4.8 176.7 65.8 37.2 102 30 5.7 15.0 3.4 263.2 59.6 22.7 103 30 7.3 12.9 10.2 176.7 139.7 79.1 107 30 5.7 15.0 13.1 263.2 229.8 87.3 111 30 7.2 10.3 4.4 143.1 60.8 42.5 112 30 7.2 10.3 7.2 143.1 100.0 69.9 114 30 7.2 10.3 7.8 143.1 108.3 75.7 118 30 5.4 12.0 7.2 222.2 133.7 60.2 133 30 5.5 12.1 9.9 220.0 180.0 81.8 143 10 3.7 13.6 9.1 367.6 245.9 66.9 143 30 7.5 9.2 5.2 122.7 69.3 56.5 144 30 3.7 13.6 11.5 367.6 310.8 84.6 178 30 3.2 8.8 5.5 275.0 171.9 62.5 192 10 5.4 12.5 10.5 231.5 194.4 84.0 194 10 5.4 12.5 11.8 231.5 218.5 94.4 194 30 8.1 11.0 4.2 135.8 51.9 38.2 194 30 3.1 4.8 4.9 154.3 157.5 102.1 194 30 3.7 14.0 6.2 378.4 167.6 44.3 196 10 3.7 14.0 9.2 378.4 248.6 65.7 196 30 1.1 9.5 4.3 863.6 390.9 45.3 199 10 2.7 10.5 9.1 388.9 337.0 86.7 199 10 3.8 13.1 10.8 344.7 284.2 82.4 205 30 3.3 9.5 2.3 287.9 70.7 24.6 206 10 3.8 13.1 8.6 344.7 226.3 65.6 207 10 5.6 9.4 8.3 167.9 148.2 88.3 207 10 7.7 13.0 5.0 168.8 64.9 38.5 207 10 5.7 12.8 6.6 225.9 116.5 51.6 207 10 2.9 12.8 5.3 441.4 182.8 41.4 207 30 3.5 3.2 91.4 207 30 3.5 13.0 6.4 371.4 184.1 49.6 216 10 3.6 10.3 4.9 286.1 136.1 47.6 218 30 2.7 10.5 3.7 388.9 137.6 35.4 223 30 3.1 4.8 5.0 154.3 160.7 104.2 224 10 3.6 6.9 3.5 191.7 97.2 50.7 225 30 3.1 4.8 7.3 154.3 234.7 152.1

TABLE XI Dose-dependent Mouse Fecal Pellet Output Test # of pellets Cpd NES Compound (mg) No. control NES % ctrl 0.3 0.5 1.0 3.0 5.0 6.0 10.0 30.0 75 235.7 93 2.7 8.3 307.4 6.2 5.5 3.2 97 6.1 11.6 190.2 14 7.5 3.5 97 4.8 10.1 210.4 9.1 10.4 2.3 102 5.3 10.7 201.9 6.9 4.5 2.22 114 3.4 10 294.1 9.6 7.7 5.4 200 3.556 8.8 247.5 8.1 8.2 5.8 207 5.2 11.4 219.2 11.4 12 4.9 207 4.8 8.6 179.2 9.4 8.6 6.7 207 3.4 10.8 317.6 7.5 5.5 3.5 207 3.6 6.5 180.6 7.3 4.8 3.4 224 2.2 9.6 436.4 7.6 7.2 4.2

TABLE XII Dose-dependent Mouse Fecal Pellet Output Test: Computed Results Cpd Compound (% control) Compound (% NES) No. 0.3 0.5 1.0 3.0 5.0 6.0 10.0 30.0 0.3 0.5 1.0 3.0 5.0 6.0 10.0 30 75 223.8 188.1 100 93 229.6 203.7 119 74.7 66.27 38.55 97 226.2 123.0 57 119 64.66 30.17 97 189.6 216.7 48 90.1 103 22.77 102 130.2 84.9 42 64.5 42.06 20.77 114 282.4 226.5 159 96 77 54 200 227.8 230.6 163 92.05 93.18 65.91 207 219.2 228.8 94.2 100 104.4 42.98 207 195.8 179.2 139.6 109 100 77.91 207 220.6 161.8 103 69.44 50.93 32.41 207 202.8 133.3 94 112.3 73.85 52.31 224 345.5 327.3 190.9 79.17 75 43.75

Example 9 In Vivo Assay: Stress-Induced Entire GI Tract Transit (6 Hour Transit Time Test)

Methods: The animals used in these studies are male CD-1 mice, ave. wt. ˜30 g. Procedure: Mice were housed in LAM under 12 h/12 h light/dark cycle, food & water ad lib. On the day before the experiments, the mice assigned to the “acclimated” (non-stressed) control group were placed into individual wire mesh-bottomed cages, provided food and water ad lib. The acclimated control group was in this new environment for 16-18 hrs prior to beginning the test. On the day of the experiment, mice assigned to experimental groups were housed in home cages were transported to procedure room and remain in their home cages until the start of the transit portion of the study. Mice were intragastrically dosed with compounds (volume remains constant at 0.1 mL/10 g body wt) by oral gavage 30 minutes before carmine (a red vital dye that does not have the drug-adsorbing properties of charcoal) is administered (0.25 mL, 6% carmine in 0.5% methylcellulose). After the carmine marker was administered each mouse was placed in the novel environment cage. One hour after administration of carmine, the fecal pellet output of each animal was recorded. At one-hour intervals thereafter the fecal pellets were examined for the presence of carmine-dye. The number of mice that excreted a carmine-containing fecal pellet at the end of each hour post carmine administration was recorded, until all mice had excreted carmine in a fecal pellet or the end of 6 hrs post carmine administration, whichever occurred first. A variant of this novel environment stress (NES) paradigm is to use the same procedures of dye and compound administrations, but to use restraint (confinement in a small plastic tube for 3 hr) as a stressor (RS=restraint stress), followed by two hours in an individual cage (total of 5 hr fecal transit time). Data is shown in Table XIII. The original data are quantal, i.e. a mouse in the treatment group either did, or did not exhibit entire GI tract transit (excrete colored feces). The mouse entire GI tract (MEGIT) transit test can thus be done in mice that are all acclimated (non-stressed), in which case the data are expressed as % control (vehicle only), or in mice that are exposed to NES or RS, in which cases the data are expressed as % of the vehicle treated NES or RS group. Data is shown in Table XIII.

TABLE XIII Mouse entire GI tract transit test (MEGIT or MEGIT-NES or MEGIT-RS* MEGIT-NES MEGIT MEGIT-RS Entire GI entire GI entire transit transit GI transit Cpd dose 6 hr 6 hr % 5 hr No. (mg) route (% NES) ctrl (% RS) 4 20 p.o. 100 18 30 p.o. 80 75 30 p.o. 125 75 60 p.o. 0 75 100 p.o. 0 227 20 p.o. 100 242 20 p.o. 100 261 20 p.o. 103.6 270 20 p.o. 112.5 289 20 p.o. 14.1 *RS = restraint stress; NES = novel environment stress

Example 10 In Vivo Assay: Upper GI Tract Transit

Methods: The animals used in these studies were male CD-1 mice, ave. wt. ˜30 g. Mice were housed under 12 h/12 h light/dark cycle, food & water ad lib. On the day of the experiment mice were assigned to experimental groups, including one vehicle-only group (=control). At 30 min before administration of carmine dye, animals were dosed with vehicle or vehicle-plus-compound, mice were returned to their home cages after drug administration. After administration of carmine, the animals were either returned to their home cages (non-stressed) or individually placed in the same metal cages as used in the fecal output or entire GI tract transit to induce a novel environment stress. One hour after administration of carmine, mice were sacrificed by cervical dislocation, the abdomen opened midventrally, the small intestine from pylorus to cecum was removed, the mesentery divided in order to lay the intestine straight & flat—without stretching. The total length of intestine and the length of carmine-dyed intestine were measured in order to determine the percent of the upper GI tract over which transit had occurred as follows: {(Length of carmine−dyed intestine)/(Total length of intestine)}×100=% upper GI transit. The data expressed were group means±SD (or s.e.m.) and data expressed as % of control. Statistics: ANOVA with the Tukey-Kramer post-hoc test and means were considered significantly different when P<0.05. Data is presented in Table XIV.

TABLE XIV Mouse Upper GI Transit Test (MUGIT) dose upper GI transit Cpd No. (mg) route (% ctrl) 8 30 p.o. 77.3 17 30 p.o. 37.3 18 10 p.o. 99.6 18 50 p.o. 69.9 18 5 p.o. 94.2 18 25 p.o. 83.0 18 100 p.o. 41.2 18 30 p.o. 37.5 18 30 p.o. 53.1 48 30 p.o. 102.1 75 30 p.o. 71.1 75 60 p.o. 56.0 75 100 p.o. 45.6 227 30 p.o. 93.9 256 30 p.o. 89.7 261 30 p.o. 87.7 270 30 p.o. 96.5 287 30 p.o. 66.4 289 30 p.o. 76.4 315 30 p.o. 94.5

Example 11 Visceral Hyperalgesia Testing

Method: Rats were chronically instrumented with EMG electrodes in the muscles of the anterior abdominal wall. Distention of an intracolonic balloon, using a barostat apparatus, evoked increases in the EMG recordings that are related to the pressure. Control responses are compared with repeat stimulation 4 hours after zymosan is administered to the colon (FIG. 1). Animals with 10% higher visceromotor responses for at least two distending pressures are considered to exhibit visceral hyperalgesia.

Compound 18 in 5 rats at repeated distentions of 40 mmHg administered at 30 mg/kg, i.p., blocked the hyperalgesic response to colorectal balloon distention following zymosan (FIG. 2 and FIG. 3).

The agonistic or antagonistic activity of the compounds of the invention at the kappa opioid receptor can be determined by known methods, for example, by the procedure described in S. Giuliani, A. Lecci, M. Tramontana, C. A. Maggi, Role of kappa opioid receptors in modulating cholinergic twitches in the circular muscle of guinea-pig colon. Brit J Pharmacol 119, 985-9 (November, 1996). 

1.-23. (canceled)
 24. A pharmaceutical dosage formulation suitable for oral administration comprising 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and a pharmaceutically acceptable carrier.
 25. The pharmaceutical dosage formulation of claim 24, wherein the formulation is present in a solid dosage form.
 26. The pharmaceutical dosage formulation of claim 25, formulated as a tablet.
 27. The pharmaceutical dosage formulation of claim 24, wherein 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid is


28. The pharmaceutical dosage formulation of claim 24, comprising about 50 mg to about 200 mg of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.
 29. The pharmaceutical dosage formulation of claim 24, comprising about 75 mg of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.
 30. The pharmaceutical dosage formulation of claim 24, comprising about 100 mg of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.
 31. The pharmaceutical dosage formulation of claim 24, wherein the pharmaceutically acceptable carrier comprises a diluent, a binder, an adhesive, a disintegrant, a lubricant, an antiadherent, a gildant, or a combination thereof.
 32. The pharmaceutical dosage formulation of claim 31, further comprising a sweetener, a flavorant, a colorant, a coating, or a combination thereof.
 33. The pharmaceutical dosage formulation of claim 31, wherein the diluent is selected from the group consisting of starch; lactose; sucrose; sucrose based diluents such as confectioner's sugar, sucrose plus 7 to 10 weight percent invert sugar, sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, 0.1 to 0.2 weight percent cornstarch and magnesium stearate; dextrose; inositol; mannitol; sorbitol; microcrystalline cellulose; dicalcium phosphate; calcium sulfate dihydrate; and calcium lactate trihydrate.
 34. The pharmaceutical dosage formulation of claim 31, wherein the binder and adhesive are selected from the group consisting of acacia gum; guar gum; tragacanth gum; sucrose; gelatin; glucose; starch; cellulosics such as methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose; and water soluble or dispersible binders such as alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose, polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates, and pregelatinized starch.
 35. The pharmaceutical dosage formulation of claim 31, wherein the disintegrant is selected from the group consisting of starches such as corn starch and potato starch; sodium starch glycolates; pregelatinized starches such as corn starch; clays such as magnesium aluminum silicate; celluloses such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose; alginates; gums such as agar, guar, locust bean, karaya, pectin, and tragacanth gum; and cross-linked polyvinylpyrrolidone.
 36. The pharmaceutical dosage formulation of claim 31, wherein the lubricant and antiadherent is selected from the group consisting of stearates such as magnesium stearate, calcium stearate and sodium stearate; stearic acid; talc waxes; stearowet; boric acid; sodium chloride; DL-leucine; carbowax 4000; carbowax 6000; sodium oleate; sodium benzoate; sodium acetate; sodium lauryl sulfate; and magnesium lauryl sulfate.
 37. The pharmaceutical dosage formulation of claim 31, wherein the glidant is selected from the group consisting of talc, cornstarch, and silica.
 38. The pharmaceutical dosage formulation of claim 24, wherein the pharmaceutically acceptable carrier is selected from mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, silica, magnesium stearate, a film coating, and a combination thereof.
 39. The pharmaceutical dosage formulation of claim 24, wherein the formulation comprises 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, silica, magnesium stearate and a film coating.
 40. A method of treating or ameliorating a δ or μ opioid receptor mediated disorder comprising administering the pharmaceutical dosage formulation of claim 24 to a subject in need of such treatment.
 41. The method of claim 40, wherein the pharmaceutical dosage formulation is administered at a frequency of one to four administrations per day.
 42. The method of claim 40, wherein the pharmaceutical dosage formulation is administered once daily.
 43. The method of claim 40, wherein the pharmaceutical dosage formulation is administered twice daily.
 44. A pharmaceutical dosage formulation for oral administration in solid form comprising 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, silica, magnesium stearate and a film coating.
 45. The pharmaceutical dosage formulation of claim 44, wherein the 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid is


46. The pharmaceutical dosage formulation of claim 45, comprising about 100 mg of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid. 